1-heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors

ABSTRACT

The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. The present invention provides a compound represented by the formula (I) wherein R 1  is a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R 2  is an optionally substituted C 6-14  aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R 3  and R 4  are each a hydrogen atom, or one of R 3  and R 4  is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R 5  is an alkyl group or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.11/991,307, filed Feb. 27, 2008, now U.S. Pat. No. 7,977,488, which is aU.S. national phase application, pursuant to 35 U.S.C. §371, of PCTinternational application Ser. No. PCT/JP2006/317408 filed Aug. 29,2006, designating the United States and published in English on Mar. 8,2007 as publication WO 2007/026916 A1, which claims priority to Japaneseapplication Nos. 2005-250356, filed Aug. 30, 2005, and 2006-100626,filed Mar. 31, 2006. The entire contents of the aforementioned patentapplications are incorporated herein by this reference.

TECHNICAL FIELD

The present invention relates to pyrrole compounds having an acidsecretion suppressive activity.

BACKGROUND ART

Proton pump inhibitors represented by omeprazole, which suppresssecretion of gastric acid for the treatment of peptic ulcer, refluxesophagitis and the like, have been widely used in clinical situations.However, the existing proton pump inhibitors are associated withproblems in terms of effect and side effects. To be specific, since theexisting proton pump inhibitors are unstable under acidic conditions,they are often formulated as enteric preparations, in which case severalhours are required before expression of the effect. In addition, sincethe existing proton pump inhibitors show inconsistent treatment effectsdue to metabolic enzyme polymorphism and drug interaction withpharmaceutical agents such as diazepam and the like, an improvement hasbeen desired.

As pyrrole compounds having a proton pump inhibitory action,EP-A-0259085 describes a compound represented by the formula:

and the like.

As compounds having a thromboxane A2 (TXA2) antagonistic action and aTXA2 synthase inhibitory action, JP-A-8-119936 describes a compoundrepresented by the formula:

wherein r1 is carboxy, protected carboxy, carboxy(lower)alkyl, protectedcarboxy(lower)alkyl, carboxy(lower)alkenyl or protectedcarboxy(lower)alkenyl, r2 is hydrogen; lower alkyl; heterocyclic(lower)alkyl optionally having aminoimino or protected aminoimino;heterocyclic (lower)alkenyl; or heterocyclic carbonyl, r3 is hydrogen orlower alkyl, r4 is acyl, r5 is hydrogen, A₀ is lower alkylene, and Z₀ isS or NH, provided when r1 is carboxy or protected carboxy, then Z₀ isNH.

Moreover, as a therapeutic drug for neoplastic diseases or autoimmunediseases, WO2004/103968 describes a compound represented by the formula:

wherein r6 is aryl, aralkyl or heteroaryl, r7 is aryl or heteroaryl, andr8 is aryl, heteroaryl or optionally substituted aminomethyl.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A pharmaceutical agent that effectively suppresses gastric acidsecretion as known proton pump inhibitors, which is improved ininstability under acidic conditions, dispersion of effects due tometabolic enzyme polymorphism and drug interaction, which are problemsof known proton pump inhibitors, is expected to show more superiortreatment effect on peptic ulcer, reflux esophagitis and the like. Asthe situation stands, however, a proton pump inhibitor capable ofsufficiently satisfying these requirements has not been found. It istherefore an object of the present invention to provide a compoundhaving a superior acid secretion suppressive effect (particularly,proton pump inhibitory effect), which has been improved in theseproblems.

Means of Solving the Problems

The present inventors have conducted various studies and found that acompound represented by the formula (I):

-   wherein R¹ is a monocyclic nitrogen-containing heterocyclic group    optionally condensed with a benzene ring or a heterocycle, the    monocyclic nitrogen-containing heterocyclic group optionally    condensed with a benzene ring or a heterocycle optionally has    substituent(s),-   R² is an optionally substituted C₆₋₁₄ aryl group, an optionally    substituted thienyl group or an optionally substituted pyridyl    group,-   R³ and R⁴ are each a hydrogen atom, or one of R³ and R⁴ is a    hydrogen atom and the other is an optionally substituted lower alkyl    group, an acyl group, a halogen atom, a cyano group or a nitro    group, and-   R⁵ is an alkyl group, or a salt thereof [hereinafter to be    abbreviated as compound (I)] unexpectedly has a very strong acid    secretion suppressive effect (proton pump inhibitory effect), and is    fully satisfactory as a pharmaceutical agent, which resulted in the    completion of the present invention.

Accordingly, the present invention relates to the following.

-   [1] A compound represented by the formula (I):

wherein R¹ is a monocyclic nitrogen-containing heterocyclic groupoptionally condensed with a benzene ring or a heterocycle, themonocyclic nitrogen-containing heterocyclic group optionally condensedwith a benzene ring or a heterocycle optionally has substituent(s), R²is an optionally substituted C₆₋₁₄ aryl group, an optionally substitutedthienyl group or an optionally substituted pyridyl group, R³ and R⁴ areeach a hydrogen atom, or one of R³ and R⁴ is a hydrogen atom and theother is an optionally substituted lower alkyl group, an acyl group, ahalogen atom, a cyano group or a nitro group, and R⁵ is an alkyl group,or a salt thereof.

-   [2] A compound represented by the formula (I):

wherein R¹ is a monocyclic nitrogen-containing heterocyclic groupoptionally condensed with a benzene ring or a heterocycle, themonocyclic nitrogen-containing heterocyclic group optionally condensedwith a benzene ring or a heterocycle optionally has substituent(s), R²is an optionally substituted C₆₋₁₄ aryl group or an optionallysubstituted thienyl group, R³ and R⁴ are each a hydrogen atom, or one ofR³ and R⁴ is a hydrogen atom and the other is an optionally substitutedlower alkyl group, an acyl group, a halogen atom, a cyano group or anitro group, and R⁵ is an alkyl group, or a salt thereof.

-   [3] The compound of the above-mentioned [1] or [2], wherein R¹ is a    monocyclic nitrogen-containing heterocyclic group.-   [4] The compound of the above-mentioned [1] or [2], wherein the    monocyclic nitrogen-containing heterocyclic group is a pyridyl    group.-   [5] The compound of the above-mentioned [1] or [2], wherein R² is a    phenyl group optionally substituted by 1 to 5 substituents selected    from (i) a halogen atom and (ii) a C₁₋₆ alkyl optionally substituted    by 1 to 5 halogen atoms.-   [6] The compound of the above-mentioned [1], wherein R² is a pyridyl    group optionally substituted by 1 to 4 substituent(s) selected from    C₁₋₆ alkyl, a halogen atom, alkoxy, cyano, acyl, nitro and amino.-   [7] The compound of the above-mentioned [1] or [2], wherein R³ and    R⁴ are each a hydrogen atom.-   [8] The compound of the above-mentioned [1] or [2], wherein R⁵ is a    methyl group.-   [9]    1-{5-(2-Fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    or a salt thereof.-   [10]    1-[4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine    or a salt thereof.-   [11]    N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine    or a salt thereof.-   [12]    1-[5-(2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine    or a salt thereof.-   [13]1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine    or a salt thereof.-   [14]    N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine    or a salt thereof.-   [15] A prodrug of the compound of the above-mentioned [1] or [2].-   [16] A pharmaceutical composition comprising the compound of the    above-mentioned [1] or [2] or a prodrug thereof.-   [17] The pharmaceutical composition of the above-mentioned [16],    which is an acid secretion inhibitor.-   [18] The pharmaceutical composition of the above-mentioned [16],    which is a potassium-competitive acid blocker.-   [19] The pharmaceutical composition of the above-mentioned [16],    which is an agent for the treatment or prophylaxis of peptic ulcer,    Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux    esophagitis, symptomatic gastroesophageal reflux disease    (symptomatic GERD), functional dyspepsia, gastric cancer, stomach    MALT lymphoma, or gastric hyperacidity; or an inhibitor of upper    gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,    hemorrhagic gastritis or invasive stress.-   [20] A method of treating or preventing peptic ulcer,    Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux    esophagitis, symptomatic gastroesophageal reflux disease    (symptomatic GERD), functional dyspepsia, gastric cancer, stomach    MALT lymphoma, or gastric hyperacidity; or a method of inhibiting    upper gastrointestinal hemorrhage due to peptic ulcer, acute stress    ulcer, hemorrhagic gastritis or invasive stress, which comprises    administering an effective amount of the compound of the    above-mentioned [1] or [2] or a prodrug thereof to a mammal.-   [21] Use of the compound of the above-mentioned [1] or [2] or a    prodrug thereof for the production of a pharmaceutical composition    for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison    syndrome, gastritis, erosive esophagitis, reflux esophagitis,    symptomatic gastroesophageal reflux disease (symptomatic GERD),    functional dyspepsia, gastric cancer, stomach MALT lymphoma, or    gastric hyperacidity; or an inhibitor of upper gastrointestinal    hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic    gastritis or invasive stress.

Effect of the Invention

Since compound (I) shows a superior proton pump inhibitory effect (whileconventional proton pump inhibitors such as omeprazole, lansoprazoleetc. form a covalent bond with a cysteine residue of H+/K+-ATPase andirreversibly inhibit the enzyme activity, since compound (I) inhibitsthe proton pump (H+/K+-ATPase) activity reversibly and in a K+antagonist inhibitory manner to consequently suppress acid secretion, itis sometimes referred to as a potassium-competitive acid blocker: P-CABor an acid pump antagonist (ACPA or APA)), it can provide a clinicallyuseful pharmaceutical composition for the prophylaxis and/or treatmentof peptic ulcer (e.g., gastric ulcer, gastric ulcer due to postoperativestress, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidalanti-inflammatory agents, ulcer due to postoperative stress etc.);Zollinger-Ellison syndrome; gastritis; erosive esophagitis; refluxesophagitis such as erosive reflux esophagitis and the like; symptomaticgastroesophageal reflux disease (symptomatic GERD) such as non-erosivereflux disease or gastroesophageal reflux disease free of esophagitisand the like; functional dyspepsia; gastric cancer (including gastriccancer associated with promoted production of interleukin-1β due to genepolymorphism of interleukin-1); stomach MALT lymphoma; gastrichyperacidity; or an inhibitor of upper gastrointestinal hemorrhage dueto peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasivestress (e.g. stress caused by major surgery requiring postoperativeintensive management, and cerebrovascular disorder, head trauma,multiple organ failure and extensive burn, each requiring intensivetreatment) and the like. Furthermore, compound (I) is used for theprophylaxis and/or treatment of airway disorders; asthma and the like,pre-anesthetic administration, eradication of Helicobacter pylori oreradication assistance and the like. Since compound (I) shows lowtoxicity and is superior in water-solubility, in vivo kinetics andefficacy expression, it is useful as a pharmaceutical composition.Moreover, since compound (I) is stable even under acidic conditions,which enables oral administration of the compound as a conventionaltablet and the like without formulating an enteric-coated preparation.This has a consequence that the preparation of tablet and the like canbe made smaller, which is advantageous in that it is easily swallowed bypatients having difficulty in swallowing, particularly the elderly andchildren. In addition, since a sustained release effect afforded byenteric-coated preparations is absent, expression of a gastric acidsecretion-suppressive action is rapid, and alleviation of symptoms suchas pain and the like is rapid.

BEST MODE FOR EMBODYING THE INVENTION

In the formula (I), as the “nitrogen-containing monocyclic heterocyclicgroup optionally condensed with a benzene ring or a heterocycle” for R¹,

-   (1) a nitrogen-containing monocyclic heterocyclic group, and-   (2) a fused ring group represented by the formula:

wherein ring A is a nitrogen-containing monocyclic heterocyclic group,ring B is a benzene ring or a heterocycle, a and b are each a bridgeheadring-constituting atom (e.g., a carbon atom, a nitrogen atom and thelike), and ═ and shows a single bond or a double bond, provided that abond to an —SO₂— group in the formula (I) is present in a ringA-constituting atom (ring atom) other than the bridgeheadring-constituting atoms a and b, can be mentioned.

As used herein, ring A needs only to contain, as a ring A-constitutingatom (ring atom), at least one (preferably 1 to 4, more preferably 1 or2) nitrogen atom, and one or both of the bridgehead ring-constitutingatoms a and b may be nitrogen atoms.

The “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle” optionally hassubstituent(s), and the substituent(s) may be present in any of ring Aand ring B.

As the “nitrogen-containing monocyclic heterocyclic group” of the“nitrogen-containing monocyclic heterocyclic group optionally condensedwith a benzene ring or a heterocycle” and the above-mentioned ring A,for example, an aromatic nitrogen-containing monocyclic heterocyclicgroup, a saturated or unsaturated non-aromatic nitrogen-containingmonocyclic heterocyclic group (aliphatic nitrogen-containing monocyclicheterocyclic group) and the like containing, as a ring-constituting atom(ring atom), at least one (preferably 1 to 4, more preferably 1 or 2)nitrogen atom can be mentioned.

As the “aromatic nitrogen-containing monocyclic heterocyclic group”, forexample, aromatic nitrogen-containing monocyclic heterocyclic groupssuch as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl (1H-imidazol-1-yl, 1H-imidazol-4-yl etc.), pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazol-1-yl, 1,2,4-triazol-4-yletc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl etc.), pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like, and N-oxide formsthereof and the like can be mentioned. Of these, a 5- or 6-memberedaromatic nitrogen-containing monocyclic heterocyclic group ispreferable, and thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyland pyridazinyl are preferable, and pyridyl is particularly preferable.

As the “saturated or unsaturated non-aromatic nitrogen-containingmonocyclic heterocyclic group”, partially reduced forms (e.g.,imidazolinyl, tetrahydropyrimidinyl and the like) of the above-mentioned“aromatic nitrogen-containing monocyclic heterocyclic group” and, forexample, azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl),morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl etc.),homopiperazinyl and the like can be mentioned. Of these, a 5- or6-membered non-aromatic nitrogen-containing monocyclic heterocyclicgroup is preferable.

As the “heterocycle” optionally condensed with a nitrogen-containingmonocyclic heterocyclic group, for example, an aromatic heterocycle ornon-aromatic heterocycle can be mentioned.

As the “aromatic heterocycle”, for example, 5- or 6-membered aromaticheteromonocyclic rings such as a furan ring, a thiophene ring, a pyrrolering, an oxazole ring, an isoxazole ring, a triazole ring, anisothiazole ring, an imidazole ring, a pyrazole ring, a 1,2,3-oxadiazolering, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan ring,a 1,2,3-thiadiazole ring, a 1,2,4-thiadiazole ring, a 1,3,4-thiadiazolering, a 1,2,3-triazole ring, a 1,2,4-triazole ring, tetrazole ring,pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazinering and the like and, for example, 8- to 12-membered aromatic fusedheterocycles such as a benzofuran ring, an isobenzofuran ring, abenzo[b]thiophene ring, an indole ring, an isoindole ring, a 1H-indazolering, a benzindazole ring, a benzoxazole ring, a 1,2-benzoisoxazolering, a benzothiazole ring, a benzopyran ring, a 1,2-benzoisothiazolering, a 1H-benzotriazole ring, a quinoline ring, an isoquinoline ring, acinnoline ring, a quinazoline ring, a quinoxaline ring, a phthalazinering, a naphthyridine ring, a purine ring, a pteridine ring, a carbazolering, an α-carboline ring, a β-carboline ring, a γ-carboline ring, anacridine ring, a phenoxazine ring, a phenothiazine ring, a phenazinering, a phenoxathiine ring, a thianthrene ring, a phenanthridine ring, aphenanthrone ring, an indolizine ring, a pyrrolo[1,2-b]pyridazine ring,a pyrazolo[1,5-a]pyridine ring, an imidazo[1,2-a]pyridine ring, animidazo[1,5-a]pyridine ring, an imidazo[1,2-b]pyridazine ring, animidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3-a]pyridine ring, a1,2,4-triazolo[4,3-b]pyridazine ring and the like (preferably, aheterocycle wherein the aforementioned 5- or 6-membered aromaticheteromonocyclic ring is condensed with a benzene ring or a heterocyclewherein the same or different two heterocycles of the aforementioned 5-or 6-membered aromatic heteromonocyclic ring are condensed, morepreferably a heterocycle wherein the aforementioned 5- or 6-memberedaromatic monocyclic heterocyclic group is condensed with a benzene ring,preferably imidazopyrimidinyl etc.) and the like can be mentioned.

As the “non-aromatic heterocycle”, for example, 3- to 8-memberedsaturated or unsaturated non-aromatic heterocycles such as an oxiranering, an azetidine ring, an oxetane ring, a thietane ring, a pyrrolidinering, a tetrahydrofuran ring, a thioran ring, a piperidine ring, atetrahydropyran ring, a morpholine ring, a thiomorpholine ring, apiperazine ring, a 3-hexahydrocyclopenta[c]pyrrole ring, ahomopiperidine ring, a homopiperazine ring and the like, or non-aromaticheterocycles wherein the double bonds of the aforementioned aromaticheteromonocyclic ring or aromatic fused heterocycle are partly orentirely saturated such as a dihydropyridine ring, a dihydropyrimidinering, a 1,2,3,4-tetrahydroquinoline ring, a1,2,3,4-tetrahydroisoquinoline ring and the like, and the like can bementioned.

As preferable nitrogen-containing monocyclic heterocyclic groupcondensed with a benzene ring or a heterocycle, for example,nitrogen-containing aromatic fused heterocyclic groups such as 8- to16-membered (preferably 8- to 12-membered) nitrogen-containing aromaticbicyclic fused heterocyclic groups such as 2- or 3-indolyl, 1- or3-isoindolyl, 1H-indazol-3-yl, 2-benzimidazolyl, 2-benzoxazolyl,3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or4-quinolyl, 1-, 3- or 4-isoquinolyl, 3- or 4-cinnolinyl, 2- or4-quinazolinyl, 2- or 3-quinoxalinyl, 1- or 4-phthalazinyl,naphthyridinyl, purinyl, pteridinyl, 1,7-phenanthrolin-2-, 3- or 4-yl,1-, 2- or 3-indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl,imidazo[1,5-a]pyridyl, imidazo[4,5-c]pyridyl,pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-c]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,2-a]pyridazinyl,[1,2,3]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-c]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl,pyrazolo[5,1-b]thiazolyl, pyrrolo[2,1-f][1,2,4]triazinyl,pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridyl, thieno[3,2-b]pyrimidinyl, thieno[2,3-b]pyridyl,thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl,pyrido[2,3-b]pyrazyl, pyrido[3,4-b]pyrazyl, pyrido[2,3-d]pyrimidinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl and the like, and thelike, and the like can be mentioned. As the nitrogen-containing aromaticfused heterocycle, fused pyridine wherein a pyridine ring is condensedwith one or two (preferably one) of the aforementioned 5- or 6-memberednitrogen-containing aromatic monocyclic heterocycles or one or two(preferably one) benzene rings (when condensed with a benzene ring, thepyridine ring has a bond), fused pyrimidine wherein a pyrimidine ring iscondensed with one or two (preferably one) of the aforementioned 5 or6-membered nitrogen-containing aromatic monocyclic heterocycles, or oneor two (preferably one) benzene rings (when condensed with a benzenering, the pyrimidine ring has a bond) and the like are preferable.

As the “non-aromatic nitrogen-containing heterocycle”, for example, 3-to 8-membered (preferably 5- or 6-membered) nitrogen-containingsaturated or unsaturated (preferably saturated) non-aromatic heterocycle(aliphatic nitrogen-containing heterocycle) such as azetidine,pyrrolidine, imidazolidine, thiazolidine, oxazolidine, piperidine,morpholine, thiomorpholine, piperazine and the like, ornitrogen-containing non-aromatic heterocycle wherein the double bonds ofthe aforementioned nitrogen-containing aromatic monocyclic heterocycleor nitrogen-containing aromatic fused heterocycle are partly or entirelysaturated, such as 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline and the like, and the like can bementioned.

As the “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle”, a 5- or 6-memberedaromatic nitrogen-containing monocyclic heterocyclic group is preferablefrom among those mentioned above. Of them, a 6-membered aromaticnitrogen-containing heterocyclic group such as pyridyl (e.g., 2-, 3- or4-pyridyl etc.), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl etc.),pyridazinyl (e.g., 3- or 4-pyridazinyl etc.) and the like is preferable,and pyridyl is particularly preferable.

As the substituent that the “nitrogen-containing monocyclic heterocyclicgroup optionally condensed with a benzene ring or a heterocycle” mayhave, (1) a halogen atom (e.g., fluorine atom, chlorine atom, bromineatom, iodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6)C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy(e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (10)C₆₋₁₄ arylthio (e.g., phenylthio, naphthylthio etc.), (11) C₇₋₁₆aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio,1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.), (12)amino, (13) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.),(14) mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.), (15) mono-C₇₋₁₆ aralkylamino (e.g., benzylaminoetc.), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.),(17) di-C₆₋₁₄ arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino (e.g., pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.)optionally containing, besides one nitrogen atom and carbon atom, 1 or 2kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.)containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, (48)C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), (50) C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl etc.) optionallyhaving 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine),(51) a C₂₋₆ alkenyl group (e.g., allyl, isopropenyl, isobutenyl,1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (52) a C₂₋₆alkynyl group (e.g., propargyl, 2-butynyl, 3-butynyl, 3-pentynyl,3-hexynyl etc.), (53) a C₁₋₆ alkyl group (e.g., hydroxymethyl,hydroxyethyl etc.) substituted by 1 to 3 hydroxy and the like can bementioned.

The substituent may be present at a substitutable position, and thenumber of the substituents is 1 to 5, preferably 1 to 3.

As the “C₆₋₁₄ aryl group” of the “optionally substituted C₆₋₁₄ arylgroup” for R², for example, phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like can bementioned.

As the substituent that the “C₆₋₁₄ aryl group” optionally has, groupssimilar to the substituents that the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for the aforementioned R¹ optionally has can be mentioned.

The number of the substituents is 1 to 5, preferably 1 to 3.

As the “thienyl group” of the “optionally substituted thienyl group” forR², 2- or 3-thienyl can be mentioned.

As the substituent that the “thienyl group” optionally has, groupssimilar to the substituents that the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for the aforementioned R¹ optionally has can be mentioned.

The number of the substituents is 1 to 4, preferably 1 to 3.

As the “pyridyl group” of the “optionally substituted pyridyl group” forR², 2-, 3- or 4-pyridyl, or bipyridyl (e.g., 2,3′-bipyridin-5-yl) can bementioned.

As the substituent that the “pyridyl group” optionally has, groupssimilar to the substituents that the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for the aforementioned R¹ optionally has can be mentioned.

The number of the substituents is 1 to 4, preferably 1 to 3.

As the “lower alkyl group” of the “optionally substituted lower alkylgroup” for R³ or R⁴, for example, C₁₋₄ alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and thelike, and the like can be mentioned.

As the substituent that the “lower alkyl group” optionally has, (1) ahalogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodineatom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) C₆₋₁₄aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy (e.g.,benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (10)C₆₋₁₄ arylthio (e.g., phenylthio, naphthylthio etc.), (11) C₇₋₁₆aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio,1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.) (12)amino, (13) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.),(14) mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.), (15) mono-C₇₋₁₆ aralkylamino (e.g., benzylaminoetc.), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.),(17) di-C₆₋₁₄ arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino optionally containing, besides one nitrogen atomand carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom (e.g., pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,hexahydroazepin-1-yl etc.), (47) a 5- to 10-membered aromaticheterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.) and the like can be mentioned.

The number of the substituents is 1 to 3.

As the “acyl group” for R³ or R⁴, an acyl group having 1 to 20 carbonatoms, which is derived from organic carboxylic acid can be mentioned.For example, C₁₋₇ alkanoyl groups (e.g., formyl; C₁₋₆ alkyl-carbonylsuch as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,heptanoyl and the like; etc.), C₆₋₁₄ aryl-carbonyl groups (e.g.,benzoyl, naphthalenecarbonyl etc.), C₁₋₆ alkoxy-carbonyl groups (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl etc.), C₆₋₁₄ aryloxy-carbonyl groups (e.g.,phenoxycarbonyl group), C₇₋₁₉ aralkyl-carbonyl groups (e.g., phenyl-C₁₋₄alkylcarbonyl such as benzylcarbonyl, phenethylcarbonyl,phenylpropylcarbonyl and the like, naphthyl-C₁₋₄ alkylcarbonyl such asbenzhydrylcarbonyl, naphthylethylcarbonyl and the like, etc.), C₇₋₁₉aralkyloxy-carbonyl groups (e.g., phenyl-C₁₋₄ alkyloxycarbonyl such asbenzyloxycarbonyl and the like, etc.), 5- or 6-memberedheterocycle-carbonyl group or condensed heterocycle-carbonyl groupsthereof (e.g., pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl and thelike; pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and thelike; imidazolylcarbonyl such as 2-, 4- or 5-imidazolylcarbonyl and thelike; triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl,1,2,4-triazol-3-ylcarbonyl and the like; tetrazolylcarbonyl such as 1H-or 2H-tetrazol-5-ylcarbonyl and the like; furylcarbonyl such as 2- or3-furylcarbonyl and the like; thienylcarbonyl such as 2- or3-thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4- or5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as 3-, 4- or5-isoxazolylcarbonyl and the like; oxadiazolylcarbonyl such as1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl,1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and thelike; triazolylcarbonyl such as 2-, 4- or 5-thiazolylcarbonyl and thelike; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl andthe like; thiadiazolylcarbonyl such as 1,2,3-thiadiazol-4- or5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-thiadiazol-3-or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl and the like;pyrrolidinylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl and the like;pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the like;pyridylcarbonyl wherein nitrogen atom is oxidized such as 2-, 3- or4-pyridyl-N-oxidocarbonyl and the like; pyridazinylcarbonyl such as 3-or 4-pyridazinylcarbonyl and the like; pyridazinylcarbonyl wherein oneor both nitrogen atoms are oxidized, such as 3-, 4-, 5- or6-pyridazinyl-N-oxidocarbonyl and the like; pyrimidinylcarbonyl such as2-, 4- or 5-pyrimidinylcarbonyl and the like; pyrimidinylcarbonylwherein one or both nitrogen atoms are oxidized, such as 2-, 4-, 5- or6-pyrimidinyl-N-oxidocarbonyl and the like; pyrazinylcarbonyl;piperidinylcarbonyl such as 2-, 3- or 4-piperidinylcarbonyl and thelike; piperazinylcarbonyl; indolylcarbonyl such as 3H-indol-2- or3-ylcarbonyl and the like; pyranylcarbonyl such as 2-, 3- or4-pyranylcarbonyl and the like; thiopyranylcarbonyl such as 2-, 3- or4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as 3-, 4-, 5-,6-, 7- or 8-quinolylcarbonyl and the like; isoquinolylcarbonyl;pyrido[2,3-d]pyrimidinylcarbonyl (e.g.,pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl (e.g.,1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6-, 1,7-, 1,8-,2,6- or 2,7-naphthyridinylcarbonyl and the like;thieno[2,3-d]pyridylcarbonyl (e.g., thieno[2,3-d]pyridin-3-ylcarbonyl);pyrazinoquinolylcarbonyl (e.g., pyrazino[2,3-b]quinolin-2-ylcarbonyl); a5- or 6-membered heterocycle-carbonyl group (e.g., chromenylcarbonyl(e.g., 2H-chromen-2- or 3-ylcarbonyl etc.) and the like) containing 1 to4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom,sulfur atom (optionally mono or dioxidized) and the like), a 5- or6-membered heterocycle-acetyl group (e.g., 5- or 6-memberedheterocycle-acetyl group containing 1 to 4 hetero atoms such as nitrogenatom (optionally oxidized), oxygen atom, sulfur atom (optionally mono ordioxidized) and the like), such as 2-pyrrolylacetyl, 3-imidazolylacetyl,5-isoxazolylacetyl and the like, and the like can be used.

As regards the substituent of acyl group, for example, when theabove-mentioned acyl group is an alkanoyl group or alkoxy-carbonylgroup, the acyl group is optionally substituted by 1 to 3 alkylthiogroups (e.g., C₁₋₄ alkylthio such as methylthio, ethylthio,n-propylthio, isopropylthio and the like, and the like), halogen (e.g.,fluorine, chlorine, bromine, iodine), alkoxy groups (e.g., C₁₋₆ alkoxysuch as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and thelike, and the like), a nitro group, alkoxy-carbonyl groups (e.g., C₁₋₆alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like,and the like), alkylamino group (e.g., mono- or di-C₁₋₆ alkylamino suchas methylamino, ethylamino, n-propylamino, n-butylamino,tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino,diethylamino, methylethylamino, di-(n-propyl)amino, di-(n-butyl)aminoand the like, and the like), alkoxyimino groups (e.g., C₁₋₆ alkoxyiminosuch as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino,n-hexyloxy-imino and the like, and the like) or hydroxyimino.

When the above-mentioned acyl group is an aryl-carbonyl group, anaryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonylgroup, a 5- or 6-membered heterocycle-carbonyl group or a 5- or6-membered heterocycle-acetyl group, it is optionally substituted by 1to 5 (preferably 1 to 3) alkyl groups (e.g., C₁₋₆ alkyl such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and thelike, C₃₋₆ cycloalkyl such as cyclohexyl and the like, and the like),alkenyl groups (e.g., C₂₋₆ alkenyl such as allyl, isopropenyl,isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like, and thelike), alkynyl groups (e.g., C₂₋₆ alkynyl such as propargyl, 2-butynyl,3-butynyl, 3-pentynyl, 3-hexynyl and the like, and the like), alkoxygroups (e.g., C₁₋₆ alkoxy such as methoxy, ethoxy, n-propoxy,tert-butoxy, n-hexyloxy and the like, and the like), acyl groups [e.g.,C₁₋₇ alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl, heptanoyl and the like; C₆₋₁₄ aryl-carbonyl such asbenzoyl, naphthalenecarbonyl and the like; C₁₋₆ alkoxy-carbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl and the like; C₆₋₁₄ aryloxy-carbonyl such asphenoxycarbonyl and the like; C₇₋₁₉ aralkyl-carbonyl such as phenyl-C₁₋₄alkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl,phenylpropylcarbonyl and the like) and the like; C₇₋₁₉aralkyloxy-carbonyl such as phenyl-C₁₋₄ alkyloxy-carbonyl (e.g.,benzyloxycarbonyl and the like) and the like, and the like], nitro,amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g., fluorine,chlorine, bromine, iodine), or alkylthio groups (C₁₋₄ alkylthio such asmethylthio, ethylthio, n-propylthio, isobutylthio and the like, and thelike).

As the “halogen atom” for R³ or R⁴, fluorine, chlorine, bromine andiodine can be mentioned.

As the “alkyl group” for R⁵, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) and the like can be mentioned.

As R¹, a “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle” (e.g., 5-6-memberedaromatic nitrogen-containing monocyclic heterocyclic groups such asthiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl and the like, and the like) optionally substituted by 1 to 3substituents selected from (i) halogen (e.g., fluorine, chlorine,bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine, iodine),(v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally substitutedby 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,bromine, iodine), (vi) amino group optionally substituted by C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.), (vii) oxo and (viii) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.) is preferable.

As R¹, especially, a “nitrogen-containing monocyclic heterocyclic groupoptionally condensed with a benzene ring or a heterocycle” (e.g., a5-6-membered aromatic nitrogen-containing monocyclic heterocyclic groupsuch as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl and the like, and the like), which is optionallysubstituted by 1 to 3 substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,chlorine, bromine, iodine), (vi) an amino group optionally substitutedby C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) oxo, is preferable.

As R¹, particularly, a 6-membered nitrogen-containing aromaticheterocyclic group (e.g., pyridyl groups (e.g., 2-, 3- or 4-pyridyletc.), pyrimidinyl groups (e.g., 2-, 4- or 5-pyrimidinyl etc.),pyridazinyl groups (e.g., 3- or 4-pyridazinyl etc.) etc.) optionallysubstituted by 1 to 3 substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,chlorine, bromine, iodine) and (vi) an amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) ispreferable, and a pyridyl group optionally substituted by 1 to 3substituents selected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) isparticularly preferable.

As R², [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano,(iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen(e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), (vii) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl etc.), (viii) a C₁₋₆ alkyl group substituted by 1 to 3hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix) C₁₋₆ alkylthio(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine,chlorine, bromine, iodine) and (x) C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl etc.),

-   [2] a thienyl group optionally substituted by 1 to 3 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl    etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen    (e.g., fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g.,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,    pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine) and (v) acetyl, or-   [3] a pyridyl group optionally substituted by 1 to 4 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,    isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi)    nitro and (vii) amino is preferable.

Of these, as R², [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano,(iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen(e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl,

-   [2] a thienyl group optionally substituted by 1 to 3 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl    etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen    (e.g., fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g.,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,    pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine) and (v) acetyl, or-   [3] a pyridyl group optionally substituted by 1 to 4 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,    isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi)    nitro and (vii) amino is preferable.

Particularly, [1] a phenyl group optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from (i) a halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogen (e.g., fluorine, chlorine, bromine, iodine),

-   [2] a thienyl group optionally substituted by 1 to 3 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), or-   [3] a pyridyl group optionally substituted by 1 to 4 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine) and (ii) lower (specifically C₁₋₆) alkyl (e.g., methyl,    ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,    pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1    to 3) halogen (e.g., fluorine, chlorine, bromine, iodine) is    preferable.

Of those mentioned above, a preferable embodiment of R² include [1] aphenyl group optionally substituted by 1 to 5 substituents selected from(i) a halogen atom and (ii) C₁₋₆ alkyl optionally substituted by 1 to 5halogen atoms, [2] a pyridyl group optionally substituted by 1 to 4substituents selected from lower (C₁₋₆) alkyl, a halogen atom, alkoxy(C₁₋₆ alkoxy), cyano, acyl (e.g., acetyl), nitro and amino, and thelike.

As R², a phenyl group, a 2-fluorophenyl group, a 2-methylphenyl group, a2-fluoropyridin-3-yl group, a 3-fluoropyridin-4-yl group, a2-chloropyridin-3-yl group, a 6-chloropyridin-3-yl group, a4-methylpyridin-3-yl group, a 2-methylpyridin-3-yl group, a3-methylpyridin-2-yl group, a 2-trifluoromethylpyridin-3-yl group and a6′-chloro-2,3′-bipyridin-5-yl group are particularly preferable.

Preferably R³ and R⁴ are each a hydrogen atom, or one of R³ and R⁴ is ahydrogen atom and the other is a C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g., acetyl,propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano groupor a nitro group. A compound wherein both R³ and R⁴ are hydrogen atomsis particularly preferable.

As R⁵, methyl or ethyl is preferable, and methyl is particularlypreferable.

The above-mentioned preferable embodiments of the substituents for R¹ toR⁵ may be optionally combined to achieve a preferable embodiment ofcompound (I).

Of compounds (I), a compound wherein

-   R¹ is a 5-6-membered aromatic nitrogen-containing monocyclic    heterocyclic group (for example, thiazolyl, imidazolyl, pyrazolyl,    pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like) or an    imidazo[1,2-a]pyrimidinyl group, which are optionally substituted by    1 to 3 substituents selected from (i) halogen (e.g., fluorine,    chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C₁₋₆    alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by    1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,    bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,    isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), (vi) amino group optionally    substituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)    and (vii) C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,    ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.);-   R² is [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionally    substituted by 1 to 5 (preferably 1 to 3) substituents selected    from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl    etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen    (e.g., fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g.,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,    pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine), (v) acetyl, (vi) C₃₋₇ cycloalkyl (e.g., cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) C₁₋₆    alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a    C₁₋₆ alkyl group substituted by 1 to 3 hydroxy (e.g., hydroxymethyl,    hydroxyethyl etc.), (ix) C₁₋₆ alkylthio (e.g., methylthio,    ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,    sec-butylthio, pentylthio, hexylthio etc.) optionally substituted by    1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine,    bromine, iodine) and (x) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,    ethylsulfinyl etc.),-   [2] a thienyl group optionally substituted by 1 to 3 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl    etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen    (e.g., fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g.,    methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,    pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine) and (v) acetyl,-   [3] a pyridyl group optionally substituted by 1 to 4 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,    isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi)    nitro and (vii) amino, or-   [4] a bipyridyl group optionally substituted by 1 to 3 halogen atoms    (e.g., fluorine, chlorine, bromine, iodine);-   R³ and R⁴ are each a hydrogen atom, or one of R³ and R⁴ is a    hydrogen atom and the other is a C₁₋₆ alkyl group (e.g., methyl,    ethyl, n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g.,    acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,    heptanoyl etc.), a halogen atom (e.g., fluorine, chlorine, bromine,    iodine), a cyano group or a nitro group;-   R⁵ is methyl or ethyl is preferable,-   a compound wherein, for example-   R¹ is a pyridyl group optionally substituted by 1 to 3 substituents    selected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl    etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen    (e.g., fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy    (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,    sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to    5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine),-   R² is [1] a phenyl group optionally substituted by 1 to 5    (preferably 1 to 3) substituents selected from (i) a halogen atom    (e.g., fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkyl    (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5    (preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,    iodine),-   [2] a thienyl group optionally substituted by 1 to 3 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)    optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,    fluorine, chlorine, bromine, iodine), or-   [3] a pyridyl group optionally substituted by 1 to 4 substituents    selected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,    iodine) and (ii) lower (specifically C₁₋₆) alkyl (e.g., methyl,    ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,    pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1    to 3) halogen (e.g., fluorine, chlorine, bromine, iodine),-   R³ and R⁴ are each a hydrogen atom, and R⁵ is methyl is particularly    preferable.

As compound (I),N-methyl-1-[5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine,1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine,N-methyl-1-[4-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methaneamine,N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine,N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine,1-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine,1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine,N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine,1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof is particularly preferable.

As a salt of compound (I), metal salt, ammonium salt, salts with organicbases, salts with inorganic bases, salts with organic acids, salts withbasic or acidic amino acids and the like can be mentioned. Preferableexamples of metal salt include alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts such as calciumsalt, magnesium salt, barium salt and the like; aluminum salt and thelike. Preferable examples of the salt with organic base include a saltwith trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferableexamples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include a salt with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includea salt with arginine, lysin, ornithine and the like. Preferable examplesof the salt with acidic amino acid include a salt with aspartic acid,glutamic acid and the like.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound contains an acidic functional group, inorganic saltssuch as alkali metal salt (e.g., sodium salt, potassium salt etc.),alkaline earth metal salt (e.g., calcium salt, magnesium salt, bariumsalt etc.) and the like, ammonium salt and the like; and when a compoundcontains a basic functional group, for example, salts with inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid and the like, or salts with organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like can be mentioned.

Compound (I) can be produced, for example, according to the methodsdescribed in JP application No. 2005-044740, Eur. J. Org. Chem., p. 2283(2001), J. Med. Chem., vol. 43, p. 1886 (2000), J. Pharm. Pharmacol.,vol. 46, p. 740 (1994), WO92/04025, J. Heterocycl. Chem., vol. 25, p.635 (1988), J. Med. Chem., vol. 14, p. 328 (1971), J. Med. Chem., vol.35, p. 4195 (1992) or Tetrahedron Lett., vol. 26, p. 4047 (1985), or amethod analogous thereto.

The production methods of compound (I) in the present invention areexplained.

The compounds (II)-(XXIV) in the formula may form salts, and as suchsalts, for example, those similar to the salts of compound (I) can bementioned.

While the compounds obtained in respective steps can be used for thenext reaction in the form of a reaction mixture or a crude product, theycan also be easily isolated and purified from the reaction mixture by aknown separation and purification means, such as recrystallization,distillation, chromatography and the like.

Compound (II) wherein R², R³ and R⁴ are as defined above, and R⁶ is aC₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and thelike can be produced according to a method known per se, such as themethod described in Chem. Pharm. Bull., vol. 49, p. 1406 (2001),Tetrahedron Letters, vol. 35, p. 5989 (1994) and the like or a methodanalogous thereto.

By reacting compound (II) with a compound represented by the formula(IIIa):

wherein R¹¹ is as defined for R¹, or the protecting group described inProtective Groups in Organic Synthesis, 3^(rd) Ed. Theodora W. Greene,Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) (e.g., phenyl,4-methylphenyl etc.), compound (IV) (each symbol in the formula is asdefined above) can be produced.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the likeand ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, and the likeor a mixed solvent thereof and the like are preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1-about 10 mol,preferably about 1-about 5 mol, per 1 mol of compound (II).

The reaction can also be carried out in the co-presence of crown ether.As the crown ether, for example, 15-crown-5-ether, 18-crown-6-ether andthe like can be mentioned. The amount of the crown ether to be used isabout 1-about 10 mol, preferably about 1-about 5 mol, per 1 mol ofcompound (II).

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about 0° C.-about 100° C.,preferably about 10° C.-about 50° C.

Compound (V) (each symbol in the formula is as defined above) can beproduced according to a method known per se, for example, the methodsdescribed in Tetrahedron Letters, vol. 13, p. 5337 (1972), Heterocycles,vol. 7, p. 77 (1977), Chem. Pharm. Bull., vol. 27, p. 2857 (1979), J.Org. Chem., vol. 62, p. 2649 (1997) and the like, or a method analogousthereto.

Compound (VI) (each symbol in the formula is as defined above) can beproduced by reacting compound (V) with N-bromosuccinimide (NBS).

N-Bromosuccinimide (NBS) is preferably used in about one equivalentamount relative to compound (V), and the reaction is preferably carriedout under an inert gas atmosphere such as nitrogen, argon and the like.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as ethers (e.g., tetrahydrofuran,diethyl ether and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like) and the like, a mixed solventthereof and the like are preferable.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min-about 24 hr, preferably about 5-12hr.

The reaction temperature is generally about −78° C. to about 25° C.,preferably about −78° C. to about 0° C.

Addition of a base is sometimes effective for the reaction. While thebase to be used is not limited as long as the reaction proceeds, anorganic base such as pyridine, picoline, lutidine and the like, and thelike can be mentioned. The amount of the organic base to be used isabout 0.001-about 10 equivalents, preferably about 0.001-about 0.1equivalent, per 1 mol of compound (V).

Compound (VII) (each symbol in the formula is as defined above) can beproduced from compound (VI) according to a method similar to the methodfor producing compound (IV) from compound (II).

Compound (IV) (each symbol in the formula is as defined above) can alsobe produced by reacting compound (VII) with a compound represented bythe formula (VIIIa):

or the formula (VIIIb):

wherein R² is as defined above, according to the method described inSynthetic Communications, vol. 11, p. 513 (1981), or a method analogousthereto.

Compound (IX) (each symbol in the formula is as defined above) can beproduced by reducing compound (IV) with a reducing agent such as lithiumaluminum hydride, diisobutyl aluminum hydride, sodium borohydride,calcium borohydride and the like. As the reducing agent, diisobutylaluminum hydride is particularly preferable. The amount of the reducingagent to be used is about 0.75-about 10 equivalents, preferably about1-about 5 equivalents, per 1 mol of compound (IV).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons (e.g., benzene, tolueneand the like) and ethers (e.g., tetrahydrofuran, diethyl ether and thelike), and the like, a mixed solvent thereof and the like arepreferable.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about −78° C. to about 100° C.,preferably about −78° C. to about 25° C.

Compound (X) (each symbol in the formula is as defined above) can besynthesized by reacting compound (IX) with an oxidant such as chromicacid-pyridine complex, pyridinium chlorochromate, manganese dioxide,sulfur trioxide-pyridine complex or tetra-n-propylammonium perruthenateand the like. As the oxidant, manganese dioxide, sulfurtrioxide-pyridine complex or tetra-n-propylammonium perruthenate ispreferable. The oxidation reaction can be carried out, for example,according to the method described in Synthesis, p. 639 (1994).

Compound (Ia) (each symbol in the formula is as defined above) can beproduced by subjecting compound (X) and a compound represented by theformula (XI):R⁵—NH₂wherein R⁵ is as defined above, to a reductive amination reactionaccording to the methods described in Shin Jikken Kagaku Koza, Vols.14-III, pp. 1380-1385 (Maruzen Press).

In addition, compound (Ia) can also be produced by the following method.

Compound (XII) (each symbol in the formula is as defined above) can beproduced from compound (VII) according to a method similar to the methodfor producing compound (IX) from compound (IV).

Compound (XIII) (each symbol in the formula is as defined above) can beproduced from compound (XII) according to a method similar to the methodfor producing compound (X) from compound (IX).

Compound (XIV) (each symbol in the formula is as defined above) can beproduced from compound (XIII) according to a method similar to themethod for producing compound (Ia) from compound (X).

Compound (XV) (each symbol in the formula is as defined above and R⁷ isan amino-protecting group) can be produced by protecting an amino groupof compound (XIV). As the amino-protecting group, tert-butylcarbamategroup (BOC group), benzylcarbamate group (Cbz group) and the like can bementioned. The protection reaction can be carried out according to amethod known per se, for example, the method described in ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., Theodora W. Greene, Peter G. M.Wuts, pp. 494-653, Wiley-Interscience (1999) and the like.

Compound (XVI) (each symbol in the formula is as defined above) can beproduced from compound (XV) according to a method similar to the methodfor producing compound (IV) from compound (VII).

Compound (Ia) (each symbol in the formula is as defined above) can beproduced by eliminating the amino-protecting group from compound (XVI)by a method known per se, for example, the method described inProtective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene,Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) and the like.

In addition, compounds (XVI) and (Ia) can also be produced by thefollowing methods.

Compound (XVII) (each symbol in the formula is as defined above) can beproduced from compound (II) according to a method similar to the methodfor producing compound (IX) from compound (IV).

Compound (XVIII) (each symbol in the formula is as defined above) can beproduced from compound (XVII) according to a method similar to themethod for producing compound (X) from compound (IX).

Compound (XIX) (each symbol in the formula is as defined above) can beproduced from compound (XVIII) according to a method similar to themethod for producing compound (Ia) from compound (X).

Compound (XX) (each symbol in the formula is as defined above) can beproduced from compound (XIX) according to a method similar to the methodfor producing compound (XV) from compound (XIV).

Compound (XVI) (each symbol in the formula is as defined above) can beproduced from compound (XX) according to a method similar to the methodfor producing compound (IV) from compound (II). Furthermore, compound(Ia) can be produced by a method similar to the aforementioned method.

In addition, compounds (XIII), (X) and (Ia) can also be produced by thefollowing methods.

Compound (XXI) (each symbol in the formula is as defined above) can beproduced from compound (V) according to a method similar to the methodfor producing compound (IV) from compound (II).

Compound (XXII) (each symbol in the formula is as defined above) can beproduced from compound (XXI) according to a method similar to the methodfor producing compound (IX) from compound (IV).

Compound (XXIII) (each symbol in the formula is as defined above) can beproduced from compound (XXII) according to a method similar to themethod for producing compound (X) from compound (IX).

Compound (XIII) (each symbol in the formula is as defined above) can beproduced from compound (XXIII) according to a method similar to themethod for producing compound (VI) from compound (V).

Compound (X) (each symbol in the formula is as defined above) can beproduced from compound (XIII) according to a method similar to themethod for producing compound (IV) from compound (VII), or from compound(XVIII) according to a method similar to the method for producingcompound (IV) from compound (II). Furthermore, compound (Ia) can beproduced according to a method similar to the aforementioned method.

Moreover, compound (XIII) and compound (XVIII) can also be synthesizedby the following method, and compound (Ia) can be further produced by amethod similar to the aforementioned method.

Compound (XXIV) (each symbol in the formula is as defined above) can beproduced according to a method known per se, for example, the methoddescribed in J. Org. Chem., vol. 55, p. 6317 (1990) and the like, or amethod analogous thereto.

Compound (XIII) (each symbol in the formula is as defined above) can beproduced from compound (XXIV) according to a method similar to themethod for producing compound (IV) from compound (II).

Compound (XVIII) (each symbol in the formula is as defined above) can beproduced from compound (XXIV) according to a method similar to themethod for producing compound (IV) from compound (VII).

When R¹¹ is a group other than the group represented by R¹ in eachcompound, the compound can be converted to compound (I) afterdeprotection by a method known per se, for example, the method describedin Protective Groups in Organic Synthesis, 3rd Ed., Theodora W. Greene,Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) and the like,using the formula (III)

wherein each symbol in the formula is as defined above, according to amethod similar to the method for producing compound (IV) from compound(II).

In each of the aforementioned reactions, when the starting compound hasan amino group, a carboxyl group or a hydroxy group as a substituent, aprotecting group generally used in peptide chemistry and the like may beintroduced into these groups. In this case, by eliminating theprotecting group as necessary after the reaction, the objective compoundcan be obtained. Introduction and elimination of these protecting groupscan be performed by a method known per se, for example, the methoddescribed in Protective Groups in Organic Synthesis, 3rd Ed., TheodoraW. Greene, Peter G. M. Wuts, Wiley-Interscience (1999) and the like.

Compound (I) can be isolated and purified by a known means such as phasetransfer, concentration, solvent extraction, fractionation, liquidconversion, crystallization, recrystallization, chromatography and thelike.

When compound (I) is obtained as a free compound, it can be converted toa desired salt by a method known per se or a method analogous thereto;conversely, when compound (I) is obtained as a salt, it can be convertedinto a free form or another desired salt by a method known per se or amethod analogous thereto.

Compound (I) may be used as a prodrug. The prodrug of compound (I) meansa compound which is converted to compound (I) under the physiologicalcondition in the body by a reaction with an enzyme, gastric acid, or thelike, that is, a compound which is converted to compound (I) byenzymatic oxidation, reduction, hydrolysis, and the like; a compoundwhich is converted to compound (I) by hydrolysis with gastric acid, andthe like.

The prodrug of compound (I) includes a compound wherein the amino groupof compound (I) is modified with acyl, alkyl or phosphoryl (e.g., acompound wherein the amino group of compound (I) is modified witheicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compoundwherein the hydroxy group of compound (I) is modified with acyl, alkyl,phosphoric acid or boric acid (e.g., a compound wherein the hydroxygroup of compound (I) is modified with acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl,etc.); a compound wherein a carboxyl group of compound (I) is modifiedto ester or amide (e.g., a compound wherein a carboxyl group of compound(I) is modified to ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like.These prodrugs can be produced from compound (I) by a method known perse.

In addition, the prodrug of compound (I) may be a compound, which isconverted to compound (I) under the physiological conditions, asdescribed in Pharmaceutical Research and Development, Vol. 7 (MoleculeDesign), pp. 163-198 (1990), published by Hirokawa Publishing Co.

When compound (I) contains an optical isomer, a stereoisomer, aregioisomer or a rotamer, either isomer and a mixture of these are alsoencompassed in compound (I). For example, when compound (I) has anoptical isomer, an optical isomer resolved from a racemate is alsoencompassed in compound (I). These isomers can be obtained as singleproducts according to synthesis and separation methods known per se(concentration, solvent extraction, column chromatography,recrystallization, etc.).

The compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and thelike) is also encompassed in the compound (I).

Compound (I) and a prodrug thereof of the present invention (hereinaftersometimes to be abbreviated as the compound of the present invention)have a proton pump inhibitory effect and effectively suppress gastricacid secretion. In addition, since they show low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiotoxicity, drug interaction, carcinogenicity and the like) and highwater-solubility, and are superior in the stability, in vivo kinetics(absorbability, distribution, metabolism, excretion and the like), andefficacy expression, they are useful as pharmaceutical agents.

The compound of the present invention is useful for the treatment orprophylaxis of peptic ulcer (e.g., gastric ulcer, gastric ulcer due topostoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused bynon-steroidal anti-inflammatory agents etc.); Zollinger-Ellisonsyndrome; gastritis; erosive esophagitis; reflux esophagitis such aserosive reflux esophagitis and the like; symptomatic gastroesophagealreflux disease (symptomatic GERD) such as non-erosive reflux disease orgastroesophageal reflux disease free of esophagitis and the like;functional dyspepsia; gastric cancer (including gastric cancerassociated with promoted production of interleukin-1β due to genepolymorphism of interleukin-1); stomach MALT lymphoma; gastrichyperacidity; upper gastrointestinal hemorrhage due to peptic ulcer,acute stress ulcer, hemorrhagic gastritis or invasive stress (e.g.stress caused by major surgery requiring postoperative intensivemanagement, and cerebrovascular disorder, head trauma, multiple organfailure and extensive burn, each requiring intensive treatment) and thelike; airway disorders; asthma and the like, pre-anestheticadministration, eradication of Helicobacter pylori or eradicationassistance and the like, in mammals (e.g., human, simian, sheep, cattle,horse, dog, cat, rabbit, rat, mouse etc.).

As used herein, the above-mentioned reflux esophagitis and symptomaticgastroesophageal reflux disease (symptomatic GERD)) are sometimescollectively referred to simply as GERD.

The content of a compound of the present invention in the pharmaceuticalcomposition of the present invention is about 0.01 to 100% by weightrelative to the entire composition. Though subject to change dependingon the administration target, administration route, target disease andthe like, its dose is about 0.5 to 1,500 mg/day, preferably about 5 to150 mg/day, based on the active ingredient, when, for example, thecompound is orally administered as an anti-ulcer agent to an adult human(60 kg). The compound of the present invention may be administered oncedaily or in 2 or 3 divided portions per day.

The compound of the present invention shows low toxicity and can beappropriately administered orally or parenterally (e.g., topical,rectal, intravenous administrations and the like) as it is or as apreparation containing a pharmaceutical composition containing apharmacologically acceptable carrier admixed according to a method knownper se, such as tablets (including sugar-coated tablets and film-coatedtablets), powder, granule, capsule (including soft capsule), orallydisintegrating tablet, orally disintegrating film, liquid, injection,suppository, sustained-release preparation, plaster and the like.Particularly, the compound of the present invention is preferablyadministered as an oral preparation in the form of tablet, granule,capsule and the like.

The pharmacologically acceptable carrier that may be used to produce thepharmaceutical composition of the present invention includes variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, dissolution aids, suspending agents, isotonizing agents,buffers and soothing agents for liquid preparations and the like. Otherordinary pharmaceutical additives such as preservatives, anti-oxidants,coloring agents, sweetening agents, souring agents, bubbling agents andflavorings may also be used as necessary.

Such “excipients” include, for example, lactose, sucrose, D-mannitol,starch, cornstarch, crystalline cellulose, light silicic anhydride,titanium oxide and the like.

Such “lubricants” include, for example, magnesium stearate, sucrosefatty acid esters, polyethylene glycol, talc, stearic acid and the like.

Such “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, starch,polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,low-substituted hydroxypropyl cellulose and the like.

Such “disintegrants” include (1) crosspovidone, (2) what is calledsuper-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical)and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starchsodium (e.g., product of Matsutani Chemical), (4) low-substitutedhydroxypropyl cellulose (e.g., product of Shin-Etsu Chemical), (5) cornstarch, and so forth. Said “crosspovidone” may be any crosslinkedpolymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer,including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinonehomopolymer, and is exemplified by Colidon CL (produced by BASF),Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP),Polyplasdon INF-10 (produced by ISP) and the like.

Such “water-soluble polymers” include, for example, ethanol-solublewater-soluble polymers [e.g., cellulose derivatives such ashydroxypropyl cellulose (hereinafter also referred to as HPC) etc,polyvinylpyrrolidone and the like], ethanol-insoluble water-solublepolymers [e.g., cellulose derivatives such as hydroxypropylmethylcellulose (hereinafter also referred to as HPMC) etc., methyl cellulose,carboxymethyl cellulose sodium and the like, sodium polyacrylate,polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.

Such “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. Such basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogencarbonate,disodium hydrogenphosphate and the like. Such basic inorganic salts ofpotassium include, for example, potassium carbonate, potassiumhydrogencarbonate and the like. Such basic inorganic salts of magnesiuminclude, for example, heavy magnesium carbonate, magnesium carbonate,magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate,magnesium silicate, magnesium aluminate, synthetic hydrotalcite[Mg₆Al₂(OH)₁₆.CO₃.4H₂O], and aluminum magnesium hydroxide. Preferred areheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide and the like. Such basic inorganic salts of calciuminclude, for example, precipitated calcium carbonate, calcium hydroxide,etc.

Such “solvents” include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike.

Such “dissolution aids” include, for example, polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Such “suspending agents” include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate etc; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl celluloseetc., and the like.

Such “isotonizing agents” include, for example, glucose, D-sorbitol,sodium chloride, glycerol, D-mannitol and the like.

Such “buffers” include, for example, buffer solutions of phosphates,acetates, carbonates, citrates etc, and the like.

Such “soothing agents” include, for example, benzyl alcohol and thelike.

Such “preservatives” include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Such “antioxidants” include, for example, sulfites, ascorbic acid,α-tocopherol and the like.

Such “coloring agents” include, for example, food colors such as FoodColor Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.;food lake colors, red oxide and the like.

Such “sweetening agents” include, for example, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Such “souring agents” include, for example, citric acid (citricanhydride), tartaric acid, malic acid and the like.

Such “bubbling agents” include, for example, sodium bicarbonate and thelike.

Such “flavorings” may be synthetic substances or naturally occurringsubstances, and include, for example, lemon, lime, orange, menthol,strawberry and the like.

The compound of the present invention may be prepared as a preparationfor oral administration in accordance with a commonly-known method, by,for example, compression-shaping with a carrier such as an excipient, adisintegrant, a binder, a lubricant, or the like, and subsequentlycoating the preparation as necessary by a commonly known method for thepurpose of taste masking, enteric dissolution or sustained release. Foran enteric preparation, an intermediate layer may be provided by acommonly known method between the enteric layer and the drug-containinglayer for the purpose of separation of the two layers.

For preparing the compound of the present invention as an orallydisintegrating tablet, available methods include, for example, a methodin which a core containing crystalline cellulose and lactose is coatedwith the compound of the present invention and, where necessary, a basicinorganic salt, and then further coated with a coating layer containinga water-soluble polymer to give a composition, which is coated with anenteric coating layer containing polyethylene glycol, further coatedwith an enteric coating layer containing triethyl citrate, still furthercoated with an enteric coating layer containing polyethylene glycol, andfinally coated with mannitol to give fine granules, which are mixed withadditives and shaped.

The above-mentioned “enteric coating layer” includes, for example, alayer consisting of a mixture of one or more kinds from aqueous entericpolymer substrates such as cellulose acetate phthalate (CAP),hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (tradename; produced by Rohm), Colicoat MAE30DP (trade name; produced byBASF), Polyquid PA30 (trade name; produced by San-yo Chemical) etc.),carboxymethylethyl cellulose, shellac and the like; sustained-releasesubstrates such as methacrylic acid copolymers (e.g., Eudragit NE30D(trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name),etc.) and the like; water-soluble polymers; plasticizers such astriethyl citrate, polyethylene glycol, acetylated monoglycerides,triacetin, castor oil and the like; and the like, and the like.

The above-mentioned “additive” includes, for example, water-solublesugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starchsaccharides, xylitol, reduced palatinose, erythritol, etc.), crystallinecellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellosesodium) etc.), low-substituted hydroxypropyl cellulose (e.g., LH-22,LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.) and thelike. Furthermore, binders, souring agents, bubbling agents, sweeteningagents, flavorings, lubricants, coloring agents, stabilizers,excipients, disintegrants etc. are also used.

The compound of the present invention may be used in combination with 1to 3 other active ingredients.

Such “other active ingredients” include, for example, anti-Helicobacterpylori active substances, imidazole compounds, bismuth salts, quinolonecompounds, and so forth.

Such “anti-Helicobacter pylori active substances” include, for example,antibiotic penicillins (e.g., amoxicillin, benzylpenicillin,piperacillin, mecillinam, ampicillin, temocillin, bacampicillin,aspoxicillin, sultamicillin, lenampicillin, etc.), antibiotic cefems(e.g., cefixime, cefaclor, etc.), antibiotic macrolides (e.g.,erythromycin, clarithromycin, roxithromycin, rokitamycin,flurithromycin, telithromycin, etc.), antibiotic tetracyclines (e.g.,tetracycline, minocycline, streptomycin, etc.), antibioticaminoglycosides (e.g., gentamicin, amikacin, etc.), imipenem and soforth. Of these substances, preferred are antibiotic penicillins,antibiotic macrolides and the like.

Such “imidazole compounds” include, for example, metronidazole,miconazole and the like.

Such “bismuth salts” include, for example, bismuth acetate, bismuthcitrate, bismuth subsalicylate and the like.

Such “quinolone compounds” include, for example, ofloxacin, ciploxacinand the like.

For eradication of Helicobacter pylori, a compound (I) or a salt thereofof the present invention with antibiotic penicillin (e.g., amoxicillinand the like) and antibiotic erythromycin (e.g., clarithromycin and thelike) is preferably used.

For the purpose of eradication of Helicobacter pylori, while thecompound of the present invention has an anti-H. pylori action(bacteriostatic action or eradication action) by itself, it can enhancethe antibacterial action of other antibiotics based on the pHcontrolling action in the stomach and the like, and also provides anassistant effect such as an eradication effect based on the action ofthe antibiotics to be used in combination.

Such “other active ingredients” and the compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injectable preparations,suppositories, sustained-release preparations, etc.], in accordance witha commonly known method, and used in combination, and may also beprepared as separate preparations and administered to the same subjectsimultaneously or at a time interval.

In addition, the compound of the present invention may be used incombination with a gastric motility enhancer, a drug acting on loweresophageal sphincter (e.g., temporary lower esophageal sphincterrelaxation suppressant etc.), ClC-2 channel opener (intestinal juicesecretion enhancer), a histamine H2 receptor antagonist, an antacid, asedative, a stomachic digestant or a non-steroidal anti-inflammatorydrug (NSAID).

As the “gastric motility enhancer”, for example, domperidone,metoclopramide, mosapride, itopride, tegaserod and the like can bementioned.

As the “a drug acting on lower esophageal sphincter”, for example,GABA-B receptor agonists such as baclofen, an optically active formthereof and the like, and the like can be mentioned.

As the “ClC-2 channel opener (intestinal juice secretion enhancer)”,lubiprostone and the like can be mentioned.

As the “histamine H2 receptor antagonist”, cimetidine, ranitidine,famotidine, roxatidine, nizatidine, lafutidine and the like can bementioned.

As the “antacid”, sodium hydrogencarbonate, aluminum hydroxide and thelike can be mentioned.

As the “sedatives”, diazepam, chlordiazepoxide and the like can bementioned.

As the “stomachic digestant”, gentiana, swertia japonica, diastase andthe like can be mentioned.

As the “non-steroidal anti-inflammatory drug”, for example, aspirin,indomethacin, ibuprofen, mefenamic acid, diclofenac, etodorac,piroxicam, celecoxib and the like can be mentioned.

A gastric motility enhancer, a drug acting on lower esophagealsphincter, a ClC-2 channel opener (intestinal juice secretion enhancer),a histamine H2 receptor antagonist, an antacid, a sedative, a stomachicdigestant or a non-steroidal anti-inflammatory drug and compound (I) ora salt thereof of the present invention may be mixed, prepared as asingle pharmaceutical composition [e.g., tablets, powders, granules,capsules (including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a staggeredmanner.

The compound of the present invention may be used in combination withthe following drugs.

(i) proton pump inhibitors, e.g., omeprazole, esomeprazole,pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;

(ii) oral antacid mixtures, e.g., Maalox®, Aludrox® and Gaviscon®;

(iii) mucosal protective agents, e.g., polaprezinc, ecabet sodium,rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper andplaunotol;

(iv) anti-gastric agents, e.g., Anti-gastrin vaccine, itriglumide andZ-360;

(v) 5-HT₃ antagonists, e.g., dolasetron, palonosetron, alosetron,azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620,ondansetron and indisetron;

(vi) 5-HT₄ agonists, e.g., tegaserod, mosapride, cinitapride andoxtriptane;

(vii) laxatives, e.g., Trifyba®, Fybogel®, Konsyl®, Isogel®, Regulan®,Celevac® and Normacol®;

(viii) GABA_(B) agonists, e.g., baclofen and AZD-3355;

(ix) GABA_(B) antagonists, e.g., GAS-360 and SGS-742;

(x) calcium channel blockers, e.g., aranidipine, lacidipine, falodipine,azelnidipine, clinidipine, lomerizine, diltiazem, gallopamil,efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol,nicardipine, isradipine, benidipine, verapamil, nitrendipine,barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine,nimodipine and fasudil;

(xi) dopamine antagonists, e.g., metoclopramide, domperidone andlevosulpiride;

(xii) Tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1antagonists, e.g., nepadutant, saredutant, talnetant,(αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), lanepitant, dapitant and3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine(2S,3S);

(xiii) nitric oxide synthase inhibitors, e.g., GW-274150, tilarginine,P54, guanidioethyldisulfide and nitroflurbiprofen;

(xiv) vanilloid receptor 1 antagonists, e.g., AMG-517 and GW-705498;

(xv) ghrelin agonists, e.g., capromorelin and TZP-101;

(xvi) AchE release stimulants, e.g., Z-338 and KW-5092.

The above-mentioned drugs (i)-(xvi) and compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a staggeredmanner.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples and Experimental Examples,which are not to be construed as limitative.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C., but it is not particularlystrictly limited. The mixing ratio of liquids shows a volume ratio.Unless otherwise specified, “%” means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60(0.063-0.200 mm) manufactured by MERCK or Fuji Silysia Chemical Ltd.Chromatorex (product name) NH (described as basic silica gel columnchromatography). The melting point was measured using Yanagimoto tracemelting point measurement apparatus or Buechi trace melting pointmeasurement apparatus (B-545), and shown without amendment. For ¹H-NMRspectrum, tetramethylsilane was used as the internal standard, andVarian Gemini-200 (200 MHz), Mercury-300 (300 MHz) spectrometer, BrukerAVANCE AV300 (300 MHz) and JNM-AL400 (400 MHz) nuclear magneticresonance apparatuses JEOL DATUM (JEOL DATUM LTD.) were used for themeasurement. The following abbreviations are used for showing themeasurement results.

s: singlet, d: doublet, dd: double doublet, dt: double triplet, t:triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, J:coupling constant, Hz: Hertz.

Reference Example 1 2-bromo-1-(2-fluorophenyl)propan-1-one

To a solution of 2′-fluoropropiophenone (25.0 g) in acetic acid (250 mL)was slowly added bromine (8.4 mL). The mixture was stirred at roomtemperature for 3 hr, and concentrated under reduced pressure. Water(200 mL) was added to the residue, and the mixture was extracted withdiisopropyl ether. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give the title compound as a yellow oil (yield 36.8 g, 97%).

¹H-NMR (CDCl₃) δ: 1.89-1.91 (3H, m), 5.27-5.34 (1H, m), 7.12-7.19 (1H,m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m), 7.88-7.93 (1H, m).

Reference Example 2 ethyl 2-cyano-4-oxo-4-phenylbutanoate

Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL),and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL)of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min.After completion of the dropwise addition, and the mixture was stirredat room temperature for 18 hr. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure. Water was added tothe residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. Excess ethylcyanoacetate contained in the obtained oil was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=8:1→1:1) to give the titlecompound as a pale-yellow oil (yield 10.41 g, 90%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.55 (1H, dd, J=16.0, 5.6 Hz),3.80 (1H, dd, J=16.0, 7.0 Hz), 4.16 (1H, dd, J=7.0, 5.6 Hz), 4.31 (2H,q, J=7.2 Hz), 7.40-7.70 (3H, m), 7.90-8.00 (2H, m).

Reference Example 3 methyl2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate

To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine(64 mL) in tetrahydrofuran (110 mL) was added a solution of2-bromo-1-(2-fluorophenyl)propan-1-one (36.8 g) in tetrahydrofuran (160mL), and the mixture was stirred at 70° C. for 20 hr. The reactionmixture was allowed to cool to room temperature, the insoluble materialwas filtered off, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=5:1) to give the title compound as a brownoil (yield 31.9 g, 80%).

¹H-NMR (CDCl₃) δ: 1.42-1.46 (3H, m), 3.82-3.85 (4H, m), 3.99-4.17 (1H,m), 7.14-7.22 (1H, m), 7.25-7.31 (1H, m), 7.55-7.63 (1H, m), 7.85-7.91(1H, m).

Reference Example 4 ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate

To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400mL) was added copper (II) bromide (92.6 g), and the mixture was heatedunder reflux for 4 hr. The reaction mixture was allowed to cool to roomtemperature and the insoluble material was filtered off. The filtratewas concentrated under reduced pressure to give crude2-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassiumcarbonate (88 g) was added to ethyl cyanoacetate (168 g), and themixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude2-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was addeddropwise over 20 min. After completion of the dropwise addition, themixture was stirred at the same temperature for 1 hr. Water (300 mL) andethyl acetate (300 mL) were added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed with10% aqueous sodium dihydrogen phosphate solution and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. Excess ethyl cyanoacetate contained in the obtained oil wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1) togive the title compound as an oil (yield 64.0 g, yield about 100%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.55-3.80 (2H, m), 4.11 (1H,t, J=6.0 Hz), 4.24-4.34 (2H, m), 7.15-7.29 (2H, m), 7.55-7.62 (1H, m),7.94 (1H, dt, J=7.5, 1.8 Hz).

Reference Example 5 ethyl2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate

2′-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform(30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) inchloroform (20 mL) was added dropwise while maintaining the reactiontemperature at not higher than 25° C. After the dropwise addition, themixture was stirred at room temperature for 1 hr, water was added to thereaction mixture and the mixture was extracted with chloroform. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, concentration under reduced pressure to give crude2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82g) was added to ethyl cyanoacetate (44.44 g), and the mixture wasstirred at 45° C. for 1 hr. A solution of crude2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) wasadded dropwise. After completion of the dropwise addition, the mixturewas stirred at the same temperature for 1 hr, and stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas concentrated under reduced pressure. Water was added to the residue,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. Excess ethyl cyanoacetate containedin the obtained oil was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil(yield 10.43 g, from 2′-(trifluoromethyl)acetophenone, yield 66%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70(1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m).

Reference Example 6 ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g)in tetrahydrofuran was blown in hydrogen chloride (28 g) underice-cooling, and the mixture was stirred at room temperature for 3 hr.Then, nitrogen was blown in to remove excess hydrogen chloride. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1) to give the title compound as a pale-yellowsolid (yield 4.24 g, 79%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=6.8 Hz), 4.33 (2H, q, J=6.8 Hz), 6.87(1H, d, J=3.2 Hz), 7.20-7.60 (5H, m), 8.79 (1H, br).

Reference Example 7 ethyl2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (19.3 g)and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=10:1→3:1)to give the title compound as a brown solid (yield 8.76 g, 53%).

¹H-NMR (CDCl₃) δ: 1.36-1.41 (3H, m), 4.33 (2H, q, J=7.2 Hz), 6.99-7.00(1H, m), 7.09-7.26 (3H, m), 7.55-7.61 (1H, m), 9.08 (1H, brs).

Reference Example 8 methyl2-chloro-5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate (31.0 g) in ethylacetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetatesolution (150 mL), and the mixture was stirred at room temperature for 2days. Water (200 mL) was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed twice withwater, and then washed with saturated aqueous sodium hydrogencarbonatesolution, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate to give the title compound as white crystals (yield 19.3g, 58%).

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.86 (3H, s), 7.12-7.42 (4H, m), 8.53(1H, brs).

Reference Example 9 ethyl 5-phenyl-1H-pyrrole-3-carboxylate

To a solution (50 mL) of ethyl2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (8.5 g) in ethanol was added10% palladium carbon (50% containing water, 0.5 g), and the mixture wasstirred under a hydrogen atmosphere at room temperature for 24 hr. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the titlecompound as a colorless solid (yield 4.50 g, 62%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.91(1H, m), 7.20-7.70 (6H, m), 8.77 (1H, br).

Reference Example 10 ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

To a solution (80 mL) of ethyl2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (8.6 g) in ethanolwas added 10% palladium carbon (50% containing water, 0.86 g), and themixture was stirred under a hydrogen atmosphere at room temperature for36 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) wasadded, and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 60 hr. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=10:1→5:1) to give the title compound as a brown solid (yield1.37 g, 18%).

¹H-NMR (CDCl₃) δ: 1.67 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz),7.03-7.05 (1H, m), 7.08-7.25 (3H, m), 7.49-7.50 (1H, m), 7.58-7.66 (1H,m), 9.22 (1H, brs).

Reference Example 11 methyl5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl2-chloro-5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (10.2 g)in methanol (200 mL) was added 10% palladium carbon (50% containingwater, 1.28 g), and the mixture was stirred under a hydrogen atmosphereat room temperature for 20 hr. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure. A saturatedaqueous sodium hydrogencarbonate solution (100 mL) was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. Recrystallization ofthe residue from ethyl acetate-hexane gave the title compound as whitecrystals (yield 6.70 g, 76%).

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 3.82 (3H, s), 7.12-7.33 (3H, m),7.42-7.49 (2H, m), 8.67 (1H, brs).

Reference Example 12 ethyl5-[(2-trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Examples 7 and 9 and using ethyl2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate, the title compoundwas obtained as colorless crystals. More specifically, a mixture ofethyl 2-cyano-4-[(2-trifluoromethyl)phenyl]-4-oxobutanoate (10.2 g) and4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) was stirred atroom temperature for 18 hr. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=10:1→3:1) to give ethyl2-chloro-5-[(2-trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate as abrown solid (yield 6.37 g, 59%). This was dissolved in ethanol (120 mL),10% palladium carbon (50% containing water, 0.5 g) was added, and themixture was stirred under a hydrogen atmosphere at room temperature for24 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to givethe title compound as a colorless solid (yield 2.89 g, 51%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.81(1H, s), 7.42-7.61 (5H, m), 8.69 (1H, br).

Reference Example 13 (5-phenyl-1H-pyrrol-3-yl)methanol

A solution (100 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.16 g)in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (24mL) of diisobutylaluminum hydride in toluene was added dropwise over 10min. The mixture was further stirred at −78° C. for 1 hr, water (2 mL)was added dropwise over 2 min, and the mixture was further stirred atroom temperature for 1 hr. The reaction mixture was filtered usingcelite and anhydrous magnesium sulfate, and concentrated under reducedpressure to give the title compound as a pale-red powder (yield 1.51 g,87%).

¹H-NMR (DMSO-d₆) δ: 4.34 (2H, d, J=5.4 Hz), 4.60 (1H, t, J=5.4 Hz),6.45-6.46 (1H, m), 6.74 (1H, br), 7.11-7.15 (1H, m), 7.31-7.35 (2H, m),7.57-7.59 (2H, m), 11.05 (1H, s).

Reference Example 14[5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol

By a similar operation as in Reference Example 13 and using methyl5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (1.63 g) and asolution (15 mL) of 1.5 mol/L diisobutylaluminum hydride in toluene, thetitle compound was obtained as white crystals (yield 1.18 g, 82%).

¹H-NMR (CDCl₃) δ: 1.30 (1H, t, J=4.8 Hz), 2.25 (3H, s), 4.61 (2H, d,J=4.8 Hz), 6.87 (1H, d, J=3.3 Hz), 7.10-7.28 (3H, m), 7.44-7.50 (1H, m),8.40 (1H, brs).

Reference Example 15 5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (45 mL) of (5-phenyl-1H-pyrrol-3-yl)methanol (1.51 g) inacetonitrile were added tetra-n-propylammonium perruthenate (0.46 g),N-methylmorpholine N-oxide (2.36 g) and molecular sieves 4A powder (4.5g), and the mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to givethe title compound as a pale-yellow powder (yield 0.92 g, 62%).

¹H-NMR (CDCl₃) δ: 6.95 (1H, m), 7.29-7.32 (1H, m), 7.40-7.44 (2H, m),7.50-7.52 (3H, m), 9.02 (1H, br), 9.84 (1H, s).

Reference Example 165-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 15 and using[5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol (1.17 g),tetra-n-propylammonium perruthenate (101 mg), N-methylmorpholine N-oxide(1.01 g) and molecular sieves 4A powder (572 mg), the title compound wasobtained as pale-pink crystals (yield 0.67 g, 58%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 7.14-7.36 (3H, m), 7.44-7.50 (2H, m),8.82 (1H, brs), 9.92 (1H, s).

Reference Example 17 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate(11.6 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/Lsolution (100 mL) of diisobutylaluminum hydride in toluene was addeddropwise over 10 min. The mixture was stirred at −78° C. for 1 hr andwater (10 mL) was added dropwise over 2 min. The mixture was allowed towarm to room temperature and the mixture was stirred for 2 hr. Thereaction mixture was filtered by adding celite and anhydrous magnesiumsulfate and concentrated under reduced pressure to give a pale-yellowoil (yield 8.3 g). To a solution (220 mL) of the obtained pale-yellowoil (8.30 g) in acetonitrile were added tetra-n-propylammoniumperruthenate (1.75 g), N-methylmorpholine N-oxide (13.5 g) and molecularsieves 4A powder (5 g), and the mixture was stirred at room temperaturefor 1.5 hr. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=7:3→1:1) to give the title compound as yellow crystals (yield5.6 g, 60%).

¹H-NMR (CDCl₃) δ: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H,m), 9.49 (1H, brs), 9.86 (1H, s).

Reference Example 185-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

A solution (28 mL) of ethyl5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.38 g) intetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (13 mL)of diisobutylaluminum hydride in toluene was added dropwise over 10 min.The mixture was further stirred at −78° C. for 1 hr, and water (3 mL)was added dropwise over 2 min. The mixture was allowed to warm to roomtemperature and the mixture was further stirred for 1 hr. The reactionmixture was filtered by adding celite and anhydrous magnesium sulfate,and the filtrate was concentrated under reduced pressure to give apale-yellow oil (yield 1.14 g). The obtained oil (1.14 g) was dissolvedin acetonitrile (50 mL), and tetra-n-propylammonium perruthenate (0.26g), N-methylmorpholine N-oxide (1.32 g) and molecular sieves 4A powder(5 g) were added to this solution. The mixture was stirred at roomtemperature for 1.5 hr. The reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the title compound as colorlesscrystals (yield 0.71 g, 61%).

¹H-NMR (CDCl₃) δ: 6.79-6.81 (1H, m), 7.46-7.78 (5H, m), 9.13 (1H, br),9.82 (1H, s).

Reference Example 19 methyl 1H-pyrrole-3-carboxylate

To a suspension of potassium tert-butoxide (17.9 g) in tetrahydrofuran(200 mL) was added dropwise a solution of p-toluenesulfonylmethylisocyanide (25.2 g) and methyl acrylate (11.8 mL) in tetrahydrofuran(200 mL) over 30 min. The reaction mixture was stirred at roomtemperature for 1 hr, water was added, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1) to give the title compound as a whitesolid (yield 6.56 g, 41%).

¹H-NMR (CDCl₃) δ: 3.82 (3H, s), 6.15 (1H, m), 6.75 (1H, m), 7.43 (1H,m), 8.50 (1H, brs).

Reference Example 20 methyl 4-methyl-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Example 19 and usingp-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate (48.5 g)and potassium tert-butoxide (76.7 g), the title compound was obtained asa pale-yellow solid (yield 16.8 g, 25%).

¹H-NMR (CDCl₃) δ: 2.29 (3H, s), 3.80 (3H, s), 6.53-6.54 (1H, m),7.36-7.38 (1H, m), 8.25 (1H, brs).

Reference Example 21 ethyl 2-methyl-1H-pyrrole-3-carboxylate

Vinyl acetate (13.4 g) was added dropwise over 2 hr to bromine (25 g)under ice-cooling with stirring. The reaction mixture was furtherstirred at the same temperature for 1 hr. Ethyl 3-oxobutanoate (18.5 g)was added, and 25% aqueous ammonia solution (44 mL) was added dropwiseover 1 hr. The reaction mixture was further stirred at room temperaturefor 30 min, water was added and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) and recrystallized from hexane to givethe title compound as a colorless solid (yield 7.56 g, 35%).

¹H-NMR (CDCl₃) δ: 1.32-1.37 (3H, m), 2.53 (3H, s), 4.24-4.31 (2H, m),6.55-6.58 (2H, m), 8.13 (1H, br).

Reference Example 22 methyl 5-bromo-1H-pyrrole-3-carboxylate

A solution (30 mL) of methyl 1H-pyrrole-3-carboxylate (3.06 g) intetrahydrofuran was cooled to −78° C., N-bromosuccinimide (4.38 g) andthen pyridine (3 drops) were added, and the mixture was stirred at thesame temperature for 1 hr. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=5:1) to give the titlecompound as a pale-yellow solid (yield 3.08 g, 62%).

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 6.58 (1H, m), 7.36 (1H, m), 8.60 (1H,brs).

Reference Example 23 methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Example 22 and using methyl4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N-bromosuccinimide (1.28g), the title compound was obtained as a pale-yellow solid (yield 489mg, 31%).

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 3.80 (3H, s), 7.37 (1H, d, J=3.0 Hz),8.40 (1H, brs).

Reference Example 24 ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.53 g) intetrahydrofuran (20 mL) was added N-bromosuccinimide (1.78 g) at −78°C., and the mixture was stirred at the same temperature for 30 min.Water and diethyl ether were added to extract the reaction mixture. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure at 5° C. or below. Theresidue was washed with hexane to give the title compound as a colorlesssolid (yield 2.26 g, 97%).

¹H-NMR (CDCl₃) δ: 1.30-1.35 (3H, m), 2.51 (3H, s), 4.22-4.29 (2H, m),6.50 (1H, s), 8.01 (1H, br).

Reference Example 25 2-hydroxy-5-pyrimidinesulfonic acid

Fuming sulfuric acid (containing 25% sulfur dioxide, 100 mL) was cooledto 0° C., and 2-aminopyrimidine (25 g) was gradually added over 1 hr.The mixture was heated to 180° C. and stirred for 40 hr. After coolingto room temperature, the mixture was poured into ice (1 kg). Theprecipitate was collected by filtration and recrystallized from water togive the title compound (yield 25.6 g, 55%).

¹H-NMR (DMSO-d₆) δ: 6.20-7.20 (2H, m), 8.71 (2H, s).

Reference Example 26 2-chloro-5-pyrimidinesulfonyl chloride

A mixture of 2-hydroxy-5-pyrimidinesulfonic acid (12.8 g) and phosphoruspentachloride (37.8 g) was stirred at 180° C. for 4 hr. After cooling toroom temperature, toluene (200 mL) was added, and the insoluble materialwas filtered off. The filtrate was washed with ice water, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was stood in a freezer for one day to givethe title compound as a pale-yellow solid (yield 14.8 g, 96%).

¹H-NMR (CDCl₃) δ: 9.19 (2H, s).

Reference Example 27 6-chloropyridazine-3-thiol

To a suspension (88 mL) of sodium hydrogensulfide (3.78 g) in ethanolwas added 3,6-dichloropyridazine (5.0 g), and the mixture was refluxedfor 1 hr. The solvent was evaporated under reduced pressure, and water(12.5 mL) was added. The mixture was adjusted to about pH 9 with 2 mol/Lsodium hydroxide solution, and the precipitate was filtered off. Thefiltrate was adjusted to about pH 2 with 6 mol/L hydrochloric acid andthe precipitate was collected by filtration to give the title compoundas a yellow solid (yield 4.74 g, 96%).

¹H-NMR (CDCl₃) δ: 6.99 (1H, d, J=9.6 Hz), 7.60 (1H, d, J=9.6 Hz).

Reference Example 28 6-chloropyridazine-3-sulfonyl fluoride

To a mixture cooled to −20° C. of methanol (10 mL) and water (10 mL)were added potassium hydrogenfluoride (16 g) and6-chloropyridazine-3-thiol (2.37 g). After stirring at the sametemperature for 20 min, chlorine was blown in for 30 min. Ice water (20mL) was added and the precipitate was collected by filtration. Theprecipitate was extracted with ethyl acetate and water. The extract waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to allowcrystallization, and the crystals were washed with hexane to give thetitle compound as a gray solid (yield 1.68 g, 53%).

¹H-NMR (CDCl₃) δ: 7.86-7.89 (1H, m), 8.17-8.19 (1H, m).

Reference Example 29

pyridin-3-ylsulfonyl chloride hydrochloride

A mixture of 3-pyridinesulfonic acid (50.0 g), phosphorus pentachloride(80.0 g) and phosphorus oxychloride (100 mL) was stirred at 120° C. for8 hr. Under a nitrogen atmosphere, the mixture was cooled to roomtemperature, and chloroform (dehydrated, 330 mL) was added. Hydrogenchloride was blown in, and the precipitated crystals were collected byfiltration and washed with chloroform (dehydrated) to give the titlecompound as a white solid (yield 54.7 g, 81%).

¹H-NMR (DMSO-d₆) δ: 8.03-8.07 (1H, m), 8.68 (1H, d, J=8.1 Hz), 8.87 (1H,d, J=5.7 Hz), 9.01 (1H, s).

Reference Example 30 6-methoxypyridin-3-ylsulfonyl chloride

5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8.3mL), and the mixture was stirred under ice-cooling. Concentratedhydrochloric acid (8.3 mL) was added, and an aqueous solution (5 mL) ofsodium nitrite (689 mg) was added dropwise over 15 min while keeping theinside temperature at not higher than 10° C. The reaction mixture wasstirred for 10 min, and gradually added at 5° C. to a mixture of cuprouschloride (280 mg) and acetic acid (17 mL) saturated in advance withsulfur dioxide gas. The mixture was allowed to gradually warm to roomtemperature until the generation of gas stopped. The reaction mixturewas concentrated to about 5 mL under reduced pressure, and theprecipitate was collected by filtration to give the title compound(yield 1.0 g, 51%) as crude crystals. This compound was used for thenext reaction without purification.

Reference Example 31 6-chloropyridin-3-ylsulfonyl chloride

Under ice-cooling, thionyl chloride (12 mL) was added dropwise over 1 hrto water (70 mL) and the mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Separately, underice-cooling, 5-amino-2-chloropyridine (5.0 g) was added to concentratedhydrochloric acid (40 mL) and the mixture was stirred. An aqueoussolution (12.5 mL) of sodium nitrite (2.88 g) was added dropwise whilekeeping the inside temperature at not higher than 5° C., and the mixturewas further stirred for 15 min. The reaction mixture was gradually addedat 5° C. to the above-mentioned sulfur dioxide-containing solution addedwith cuprous chloride (70 mg). Under ice-cooling, the mixture wasfurther stirred for 30 min. The precipitate was collected by filtration,and washed with water and ethanol to give the title compound (yield 4.79g, 58%).

¹H-NMR (CDCl₃) δ: 7.60-7.63 (1H, m), 8.24-8.27 (1H, m), 9.03-9.04 (1H,m).

Reference Example 32 2-chloro-3-pyridinesulfonyl chloride

Under ice-cooling, thionyl chloride (24 mL) was added dropwise over 1 hrto water (140 mL) and the mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Separately, underice-cooling, 3-amino-2-chloropyridine (10 g) was added to concentratedhydrochloric acid (80 mL) and the mixture was stirred. An aqueoussolution (25 mL) of sodium nitrite (5.75 g) was added dropwise whilekeeping the inside temperature at not higher than 5° C., and the mixturewas further stirred for 15 min. The reaction mixture was gradually addedat 5° C. to the above-mentioned sulfur dioxide-containing solution addedwith cuprous chloride (140 mg). Under ice-cooling, the mixture wasfurther stirred for 30 min, and the precipitate was collected byfiltration and washed with water and ethanol to give the title compound(yield 6.99 g, 42%).

¹H-NMR (CDCl₃) δ: 7.54-7.56 (1H, m), 8.46-8.48 (1H, m), 8.71-8.73 (1H,m).

Reference Example 33 6-chloro-5-methylpyridine-3-amine

Reduced iron (793 mg) was added to an aqueous solution (25 mL) ofammonium chloride (1.27 g), and the mixture was stirred at roomtemperature for 5 min. A solution (10 mL) of2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was addeddropwise over 10 min. The reaction mixture was stirred at 40° C. for 20min and at 50° C. for 1.5 hr and further refluxed for 1 hr. The reactionmixture was filtered through celite, and celite was washed withmethanol. Methanol was mostly removed by concentration under reducedpressure, and saturated aqueous sodium hydrogencarbonate solution wasadded. The mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) togive the title compound as a solid (yield 280 mg, 42%).

¹H-NMR (CDCl₃) δ: 3.62 (2H, br), 6.88-6.89 (1H, m), 7.70-7.71 (1H, m).

Reference Example 34 6-chloro-5-methylpyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (0.6 mL) was added dropwise over 30min to water (3.4 mL). The mixture was stirred at room temperature for12 hr to give a sulfur dioxide-containing solution. Separately, underice-cooling, 6-chloro-5-methylpyridine-3-amine (278 mg) was added toconcentrated hydrochloric acid (6 mL) and the mixture was stirred. Anaqueous solution (2 mL) of sodium nitrite (148 mg) was added dropwisewhile keeping the inside temperature at not higher than 5° C., and themixture was further stirred for 15 min. The reaction mixture wasgradually added at 5° C. to the above-mentioned sulfurdioxide-containing solution added with cuprous chloride (5 mg). Underice-cooling, the mixture was further stirred for 30 min, and theprecipitate was collected by filtration and washed with water to givethe title compound as a pale-yellow solid (yield 271 mg, 62%).

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 8.15 (1H, s), 8.86 (1H, s).

Reference Example 35 2-pyridinesulfonyl chloride

Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid(50 mL) and the mixture was stirred. Sodium hypochlorite solution(chlorine content 5%, 126 mL) was added dropwise over 1.5 hr, and themixture was further stirred at the same temperature for 30 min. Thereaction mixture was diluted with water (100 mL), and extracted withdichloromethane. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound as a colorless oil (yield 2.45 g, 77%).

¹H-NMR (CDCl₃) δ: 7.69-7.71 (1H, m), 8.06-8.14 (2H, m), 8.83-8.85 (1H,m).

Reference Example 36 ethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.60 g) was dissolved intetrahydrofuran (50 mL), sodium hydride (60% in oil, 446 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(2.24 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 2-Chloro-5-pyrimidinesulfonyl chloride (2.06 g)was added and the reaction mixture was stirred at room temperature for 1hr. Water was added, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to give the title compound as a yellowoil (yield 2.03 g, 70%).

¹H-NMR (CDCl₃) δ: 1.35-1.39 (3H, m), 4.30-4.37 (2H, m), 6.64 (1H, s),7.22-7.26 (2H, m), 7.37-7.51 (3H, m), 8.04 (1H, s), 8.37 (2H, s).

Reference Example 37 ethyl1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (87mg) and 2 mol/L trimethylaluminum-hexane solution (1.5 mL) were added toa solution of ethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(588 mg) in tetrahydrofuran (20 mL) with stirring. The mixture wasstirred at room temperature for 15 min and 2 mol/Ltrimethylaluminum-hexane solution (1 mL) was added. After stirring atthe same temperature for 20 min, ice water (100 mL) and ammoniumchloride (2.0 g) were added, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as apale-yellow oil (yield 350 mg, 63%).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 2.77 (3H, s), 4.29-4.36 (2H, m),6.61 (1H, s), 7.21-7.26 (2H, m), 7.37-7.49 (3H, m), 8.06 (1H, s), 8.41(2H, s).

Reference Example 38 ethyl1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

7 mol/L ammonia-methanol solution (1.0 mL) was added to a solution ofethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(392 mg) in tetrahydrofuran (10 mL) with stirring. The mixture wasstirred at room temperature for 20 min, saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound as a colorless solid (yield 373 mg, yield about100%).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 4.28-4.36 (2H, m), 5.60 (2H, br),6.59 (1H, s), 7.26-7.46 (5H, m), 8.02-8.03 (3H, m).

Reference Example 39 ethyl1-(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate

A mixture of ethyl1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(373 mg), 2-bromo-1,1-diethoxyethane (394 mg) and acetic acid (20 mL)was stirred in a microwave reaction apparatus at 130° C. for 30 min.After cooling to room temperature, the solvent was evaporated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→ethyl acetate) to give the title compound as abrown solid (yield 157 mg, 40%).

¹H-NMR (CDCl₃) δ: 1.35-1.40 (3H, m), 4.30-4.37 (2H, m), 6.61 (1H, s),7.17-7.49 (2H, m), 7.26-7.49 (4H, m), 7.94 (1H, s), 7.99 (1H, s), 8.11(1H, s), 8.38 (1H, s).

Reference Example 40 ethyl5-phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.06 g) was dissolved intetrahydrofuran (30 mL), sodium hydride (60% in oil, 300 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(1.52 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 6-Chloropyridazine-3-sulfonyl fluoride (1.28 g)was added and the reaction mixture was stirred at room temperature for30 min. Hydrazine (1.60 g) was added and the reaction mixture wasstirred at room temperature for 15 min. Saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (30 mL),manganese dioxide (75% chemically treated product, 5.0 g) was added, andthe mixture was stirred at room temperature for 10 min. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound (yield 613 mg,yield 24% (containing impurity)).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 4.29-4.36 (2H, m), 6.61 (1H, s),7.11-7.22 (2H, m), 7.24-7.51 (5H, m), 8.20 (1H, s), 9.28-9.30 (1H, s).

Reference Example 41 methyl5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 1.1 g) was washed with hexane, and suspendedin N,N-dimethylformamide (50 mL). A solution (10 mL) of methyl5-bromo-1H-pyrrole-3-carboxylate (5.0 g) in N,N-dimethylformamide wasadded to the suspension at 0° C. After stirring at 0° C. for 30 min, asolution of benzenesulfonyl chloride (3.3 mL) in N,N-dimethylformamide(5 mL) was added, and the reaction mixture was stirred at roomtemperature for 1 hr. Water was added, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=5:1) to give the title compound as a colorlesssolid (yield 8.5 g, 99%).

¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 6.68 (1H, d, J=2.1 Hz), 7.55-7.60 (2H,m), 7.67-7.72 (1H, m), 7.96-7.99 (2H, m), 8.08 (1H, d, J=2.1 Hz).

Reference Example 42 methyl5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 202 mg) was washed with hexane and suspendedin N,N-dimethylformamide (10 mL). A solution (10 mL) of methyl5-bromo-4-methyl-1H-pyrrole-3-carboxylate (1.0 g) inN,N-dimethylformamide was added dropwise at −78° C. After completion ofthe dropwise addition, the reaction mixture was stirred at roomtemperature for 30% min and added dropwise to an ice-cooled solution (10mL) of benzenesulfonyl chloride (0.71 mL) in N,N-dimethylformamide.After completion of the dropwise addition, the reaction mixture wasstirred at room temperature for 1 hr, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the title compound as a brown solid (yield 1.13 g, 69%).

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 3.79 (3H, s), 7.45-7.70 (3H, m),7.85-7.95 (2H, m), 8.06 (1H, s).

Reference Example 43 ethyl2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Example 41 and using ethyl2-methyl-1H-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil,2.58 g) and benzenesulfonyl chloride (7.8 mL), the title compound wasobtained as white crystals (yield 14.3 g, 85%).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.62 (3H, s), 4.24 (2H, q,J=7.2 Hz), 6.63 (1H, d, J=3.3 Hz), 7.30 (1H, d, J=3.3 Hz), 7.51-7.57(2H, m), 7.62-7.68 (1H, m), 7.81-7.84 (2H, m).

Reference Example 44 ethyl5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate (2.26 g) was dissolvedin tetrahydrofuran (100 mL), sodium hydride (60% in oil, 1.16 g) wasadded and the mixture was stirred at room temperature for 15 min.15-Crown-5 (5.90 mL) was added and the mixture was further stirred atthe same temperature for 15 min. 3-Pyridinesulfonyl chloridehydrochloride (3.13 g) was added and the reaction mixture was stirred atroom temperature for 1 hr. Saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→7:3) to give the title compound as a yellow oil (yield 2.31g, 64%).

¹H-NMR (CDCl₃) δ: 1.24-1.34 (3H, m), 2.94 (3H, s), 4.23-4.30 (2H, m),6.69 (1H, s), 7.51-7.55 (1H, m), 8.17-8.21 (1H, m), 8.88-8.91 (1H, m),9.14 (1H, m).

Reference Example 45 ethyl2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

A suspension of ethyl5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.26g), phenylboronic acid (1.54 g),dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate(1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 80°C. for 40 min. After cooling, the reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The organic layer wasseparated from the filtrate, washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→6:4) to give the title compound as acolorless oil (yield 2.39 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.30-1.34 (3H, m), 2.92 (3H, s), 4.23-4.30 (2H, m),6.59 (1H, s), 7.23-7.39 (4H, m), 7.50-7.68 (2H, m), 8.22-8.25 (1H, m),8.61-8.62 (1H, m), 8.75-8.77 (1H, m).

Reference Example 46 [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (80 mL) of methyl5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7.1 g) intetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (42 mL) ofdiisobutylaluminum hydride in toluene was added dropwise over 30 min andthe mixture was further stirred at −78° C. for 1 hr. 1 mol/Lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound as a brown oil (yield 7.1 g,about 100%).

¹H-NMR (CDCl₃) δ: 1.62 (1H, brs), 4.51 (2H, s), 6.33-6.34 (1H, m),7.44-7.45 (1H, m), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 7.93-7.97 (2H,m).

Reference Example 47[2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

By a similar operation as in Reference Example 13 and using ethyl2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (8.05 g) and 1.5mol/L diisobutylaluminum hydride toluene solution (55 mL), the titlecompound was obtained as white crystals (yield 6.61 g, 96%).

¹H-NMR (CDCl₃) δ: 1.37 (1H, brs), 2.29 (3H, s), 4.42 (2H, brs), 6.29(1H, d, J=3.6 Hz), 7.30 (1H, d, J=3.6 Hz), 7.49-7.55 (2H, m), 7.58-7.64(1H, m), 7.78-7.81 (2H, m).

Reference Example 485-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (80 mL) of[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) inacetonitrile were added tetra-n-propylammonium perruthenate (0.63 g),N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4Apowder (3.5 g), and the mixture was stirred at room temperature for 2hr. The reaction mixture was filtered, and the filtrate was concentratedunder reduced pressure. Water was added to the residue, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=4:1) to give the titlecompound as a colorless solid (yield 4.6 g, 71%).

¹H-NMR (CDCl₃) δ: 6.73 (1H, d, J=2.1 Hz), 7.57-7.63 (2H, m), 7.70-7.75(1H, m), 7.98-8.02 (2H, m), 8.10 (1H, d, J=2.1 Hz), 9.77 (1H, s).

Reference Example 495-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 17 and using methyl5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate, the titlecompound was obtained as a colorless solid (1.78 g, 54%).

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 7.50-7.62 (3H, m), 7.91-7.96 (2H, m),8.04 (1H, s), 9.77 (1H, s).

Reference Example 50 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

A suspension of5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g),phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium(0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30mL)-water (10 mL) was stirred at 100° C. for 1 hr. 8 mol/L aqueoussodium hydroxide solution (15 mL) was added, and the mixture was stirredat 90° C. for 3 hr. After cooling, the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1), and the obtained solid was washed withhexane to give the title compound as a pale-yellow solid (yield 815 mg,69%).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 7.34-7.48 (6H, m), 8.58 (1H, br), 9.91(1H, s).

Reference Example 512-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol(6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was addedsulfur trioxide•pyridine complex (4.57 g), and the mixture was stirredat room temperature for 12 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=2:1) to give a white titlecompound (yield 5.27 g, 84%).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 6.65 (1H, d, J=3.6 Hz), 7.35 (1H, d,J=3.6 Hz), 7.55-7.61 (2H, m), 7.66-7.71 (1H, m), 7.85-7.88 (2H, m), 9.89(1H, s).

Reference Example 52 2-methyl-1H-pyrrole-3-carbaldehyde

To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(4.59 g) in tetrahydrofuran (20 mL) and methanol (5 mL) was added 8mol/L aqueous sodium hydroxide solution (2.5 mL) at 0° C., and thereaction mixture was stirred at the same temperature for 30 min. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as a whitesolid (yield 1.06 g, 54%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 6.58-6.59 (1H, m), 6.65-6.67 (1H, m),8.52 (1H, brs), 9.89 (1H, s).

Reference Example 532-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 44 and using2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil,1.20 g), 15-crown-5 (6.0 mL) and pyridin-3-ylsulfonyl chloridehydrochloride (3.22 g), the title compound was obtained as whitecrystals (yield 1.10 g, 44%).

¹H-NMR (CDCl₃) δ: 2.66 (3H, s), 6.68 (1H, d, J=3.9 Hz), 7.34 (1H, d,J=3.9 Hz), 7.51-7.55 (1H, m), 8.09-8.13 (1H, m), 8.89-8.91 (1H, m),9.10-9.11 (1H, m), 9.90 (1H, s).

Reference Example 545-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) inN,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at0° C., and the mixture was stirred at room temperature for 1 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as whitecrystals (yield 675 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.89 (3H, s), 6.18 (1H, s), 7.53-7.57 (1H, m),8.21-8.26 (1H, m), 8.91-8.93 (1H, m), 9.17-9.18 (1H, m), 9.92 (1H, s).

Reference Example 555-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg)was dissolved in absolute tetrahydrofuran (20 mL) and sodium hydride(60% in oil, 240 mg) was added while stirring at room temperature. Afterstirring at the same temperature for 15 min, 15-crown-5 (1.21 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. Pyridin-3-ylsulfonyl chloride hydrochloride (642 mg) was added,and the mixture was further stirred at the same temperature for 30 min.The reaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) togive the title compound as a brown solid (yield 470 mg, 75%).

¹H-NMR (CDCl₃) δ: 6.60 (1H, d, J=1.8 Hz), 7.15-7.19 (2H, m), 7.25-7.37(3H, m), 7.42-7.48 (1H, m), 7.53-7.57 (1H, m), 8.13 (1H, d, J=1.8 Hz),8.49-8.50 (1H, m), 8.74-8.76 (1H, m), 9.90 (1H, s).

Reference Example 561-[(6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg)was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride(60% in oil, 200 mg) was added at room temperature while stirring. Afterstirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, andthe mixture was stirred at the same temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed successively withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the titlecompound as an oil (yield 59 mg, 17%).

¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 6.59-6.62 (2H, m), 7.19-7.44 (6H, m),8.08-8.10 (2H, m), 9.88 (1H, s).

Reference Example 571-(6-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg)was dissolved in absolute tetrahydrofuran (15 mL), and sodium hydride(60% in oil, 180 mg) was added at room temperature while stirring. Afterstirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. 6-Chloropyridin-3-ylsulfonyl chloride (827 mg) was added, andthe mixture was further stirred at the same temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) togive the title compound as an oil (yield 762 mg, 73%).

¹H-NMR (CDCl₃) δ: 6.62 (1H, s), 7.19-7.49 (7H, m), 8.09 (1H, s),8.24-8.26 (1H, m), 8.90 (1H, s).

Reference Example 581-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 55 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60%in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonylchloride (716 mg), the title compound was obtained as an amorphous form(yield 716 mg, 69%).

¹H-NMR (CDCl₃) δ: 6.64 (1H, s), 6.70-6.90 (1H, m), 7.05-7.08 (2H, m),7.15-7.18 (2H, m), 7.26-7.32 (1H, m), 7.55-7.59 (1H, m), 8.26 (1H, s),8.44-8.46 (1H, m), 9.94 (1H, s).

Reference Example 591-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 55 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (342% mg), sodium hydride (60%in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonylchloride (554 mg), the title compound was obtained as a yellow solid(yield 390 mg, 56%).

¹H-NMR (CDCl₃) δ: 6.68 (1H, s), 7.22-7.26 (2H, m), 7.39-7.52 (3H, m),8.09 (1H, s), 8.35 (2H, s), 9.91 (1H, s).

Reference Example 601-[(6-chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 55 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 60 mg), 15-crown-5 (0.30 mL) and6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), the titlecompound was obtained as a solid (yield 244 mg, 68%).

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 6.62 (1H, s), 7.20-7.26 (3H, m),7.35-7.49 (3H, m), 8.09 (1H, s), 8.13 (1H, m), 9.90 (1H, s).

Reference Example 612-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

A solution (15 mL) of ethyl2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (980mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (5.3mL) of diisobutylaluminum hydride in toluene was added dropwise over 10min., and the mixture was warmed to 0° C. over 2 hr. Water (100 mL) andethyl acetate (20 mL) were added, and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was filtered throughcelite, and the organic layer was collected, washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was dissolved in acetonitrile solution (25mL), tetra-n-propylammonium perruthenate (93 mg), N-methylmorpholineN-oxide hydrate (466 mg) and molecular sieves 4A powder (500 mg) wereadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was concentrated under reduced pressure, and ethylacetate (30 mL) was added to the residue. The mixture was filteredthrough celite, and celite was washed with ethyl acetate. The filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1)to give the title compound as a yellow oil (yield 235 mg, 27%).

¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 6.51 (1H, s), 7.18-7.42 (6H, m),7.59-7.64 (1H, m), 8.60 (1H, s), 8.77-8.79 (1H, m), 10.03 (1H, s).

Reference Example 621-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Under a nitrogen atmosphere, a solution of ethyl1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(280 mg) in tetrahydrofuran (20 mL) was cooled to −78° C., a 1.5 mol/Lsolution (3.0 mL) of diisobutylaluminum hydride in toluene was addedwhile stirring. After stirring at the same temperature for 15 min, themixture was allowed to warm to −40° C. over 30 min. Water (50 mL) wasadded, and after stirring at the same temperature for 5 min, the mixturewas allowed to warm to 0° C. over 10 min. Ethyl acetate (30 mL) wasadded, and after stirring at the same temperature for 15 min, themixture was stirred at room temperature for 20 min. A gel-like mixturewas filtered through celite, and celite was washed with ethyl acetate.The organic layer was separated from the filtrate, washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was dissolved in tetrahydrofuran (50 mL),manganese dioxide (75% chemically treated product, 3.0 g) was added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as apale-yellow solid (yield 150 mg, 61%).

¹H-NMR (CDCl₃) δ: 2.78 (3H, s), 6.64 (1H, s), 7.21-7.26 (2H, m),7.36-7.51 (3H, m), 8.10 (1H, s), 8.40 (2H, s), 9.90 (1H, s).

Reference Example 635-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (96 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 503mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for30 min. Pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added,and the mixture was further stirred for 3 hr. The reaction mixture wasdiluted with saturated brine, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→2:3) and crystallized from diisopropylether-ethyl acetate (4:1) to give the title compound as colorlesscrystals (yield 680 mg, 82%).

¹H-NMR (CDCl₃) δ: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 7.16-7.19(2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-7.73 (1H, m), 8.14(1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81-8.83 (1H, m), 9.91 (1H, s).

Reference Example 641-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution (36 mL) of5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (240 mg) intetrahydrofuran was added sodium hydride (60% in oil, 201 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (1.11 g)was added dropwise and the mixture was stirred for 30 min.Pyridine-3-sulfonyl chloride hydrochloride (537 mg) was added, and themixture was further stirred for 3 hr. The reaction mixture was dilutedwith saturated brine, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→2:3) and crystallized from diisopropyl ether to give thetitle compound as colorless crystals (yield 380 mg, about 100%).

¹H-NMR (CDCl₃) δ: 6.69 (1H, d, J=1.8 Hz), 7.34-7.38 (1H, m), 7.44-7.48(1H, m), 7.61-7.69 (4H, m), 8.16 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4Hz), 8.81 (1H, m), 9.91 (1H, s).

Reference Example 654-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg) was dissolved intetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(0.30 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (231mg) was added and the reaction mixture was stirred at room temperaturefor 1 hr. Water was added, and the mixture was extracted with ethylacetate. The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as acolorless solid (yield 172 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 7.01-7.04 (2H, m), 7.26-7.55 (5H, m),8.07 (1H, s), 8.47 (1H, m), 8.75-8.78 (1H, m), 9.97 (1H, s).

Reference Example 664-methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 65 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 2-pyridinesulfonylchloride (231 mg) instead of 3-pyridinesulfonyl chloride hydrochloride,the title compound was obtained as an amorphous form (yield 262 mg,80%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 6.92-6.95 (2H, m), 7.21-7.49 (5H, m),7.65-7.69 (1H, m), 8.14 (1H, s), 8.64-8.65 (1H, m), 9.98 (1H, s).

Reference Example 671-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 65 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl chloride (253 mg), the titlecompound was obtained as a colorless solid (yield 294 mg, 86%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.33 (3H, s), 3.40 (3H, s), 6.48 (1H,s), 7.11-7.14 (2H, m), 7.26-7.41 (3H, m), 8.08 (1H, s), 9.93 (1H, s).

Reference Example 681-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 65 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl chloride (298 mg), thetitle compound was obtained as an oil (yield 379 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.74 (3H, s), 2.04 (3H, s), 3.69 (3H, s), 7.04-7.07(2H, m), 7.28-7.38 (3H, m), 8.09 (1H, s), 9.96 (1H, s).

Reference Example 691-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 65 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl chloride (275 mg), the titlecompound was obtained as an oil (yield 27.8 mg, 8%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.10 (3H, s), 2.59 (3H, s), 7.07-7.10(2H, m), 7.31-7.40 (3H, m), 8.02 (1H, s), 9.96 (1H, s).

Reference Example 705-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 65 and using5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodiumhydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (476 mg), the title compoundwas obtained as white crystals (yield 440 mg, 87%).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 6.98-7.04 (1H, m), 7.13-7.24 (2H, m),7.33-7.38 (1H, m), 7.43-7.51 (1H, m), 7.65-7.69 (1H, m), 8.09 (1H, s),8.54-8.55 (1H, m), 8.80-8.82 (1H, m), 9.98 (1H, s).

Reference Example 711-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

To a solution (60 mL) of5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.5 g) in methanolwere added methylammonium chloride (7.5 g) and sodium cyanoborohydride(2.4 g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium hydrogencarbonate solution was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound as a brown oil (yield4.4 g, about 100%).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 2.98 (1H, brs), 3.66 (2H, s), 6.35 (1H,d, J=2.4 Hz), 7.51-7.57 (3H, m), 7.61-7.68 (1H, m), 7.93-7.97 (2H, m).

Reference Example 72 tert-butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8mL), and the mixture was stirred at room temperature for 14 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogencarbonate solution andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=4:1) to give the titlecompound as a colorless oil (yield 3.4 g, 73%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs), 6.24(1H, brs), 7.35 (1H, brs), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m),7.90-7.94 (2H, m).

Reference Example 73 tert-butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate

tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) andmethanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL)was added dropwise at not more than 10° C. After stirring at the sametemperature for 4 hr, water was added to the residue and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as a pale-yellow oil (yield 410 mg, 61%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.79 (3H, s), 4.17 (2H, s), 6.09 (1H,brs), 6.64 (1H, brs), 8.07 (1H, br).

Reference Example 74 tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a suspension (10 mL) of sodium hydride (60% in oil, 204 mg) intetrahydrofuran was added a solution (3 mL) of tert-butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (410 mg) inN,N-dimethylformamide at 0° C., and 15-crown-5 (938 mg) andpyridin-3-ylsulfonyl chloride hydrochloride (456 mg) were added at thesame temperature. After stirring at room temperature for 2 hr, water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1→3:1) to give the title compound as apale-yellow powder (yield 522 mg, 85%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (3H, brs), 4.18 (2H, brs), 6.28(1H, brs), 7.35 (1H, brs), 7.48-7.52 (1H, m), 8.18-8.22 (1H, m),8.85-8.88 (1H, m), 9.12-9.13 (1H, m).

Reference Example 75 tert-butyl{[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-(2-Chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (443mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution(0.74 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasadded to a solution of sodium borohydride (97 mg) in methanol (2.5 mL),and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (1.40 g), sodiumhydrogencarbonate (0.54 g) and water (13 mL) were added, and the mixturewas stirred at room temperature for 20 min. The reaction mixture wasdiluted with ethyl acetate, washed successively with saturated aqueoussodium hydrogencarbonate solution, water and saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the titlecompound as a solid (yield 361 mg, 61%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.87 (3H, s), 4.29 (2H, s), 6.30-6.32(1H, m), 6.95-7.00 (1H, m), 7.06-7.33 (5H, m), 7.51-7.56 (2H, m),8.38-8.41 (1H, m).

Reference Example 76 tert-butyl{[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(244 mg) was dissolved in absolute tetrahydrofuran (6.8 mL), a 2 mol/Lsolution (0.34 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 4 hr. The reaction mixturewas added to a solution of sodium borohydride (51 mg) in methanol (3mL), and the mixture was stirred at the same temperature for 3 min.di-tert-Butyl bicarbonate (654 mg) was added, and water (5 mL) andsodium hydrogencarbonate (420 mg) were added 3 min later. The mixturewas further stirred at room temperature for 30 min, water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as anoil (yield 247 mg, 77%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.28 (3H, s), 2.82 (3H, s), 4.24-4.28(2H, m), 6.15 (1H, s), 7.23-7.42 (7H, m), 8.15 (1H, s).

Reference Example 77 tert-butyl({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

1-[(6-Chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(1.27 g) was dissolved in absolute tetrahydrofuran (20 mL), a 2 mol/Lsolution (2.1 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas added to a solution of sodium borohydride (277 mg) in methanol (10mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine and dried over anhydrous magnesium sulfate.di-tert-Butyl bicarbonate (3.99 g) was added, and the solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), sodium hydrogencarbonate (1.53 g) and water (36mL) was added, and the mixture was stirred at room temperature for 30min. The reaction mixture was diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→3:1) to give the title compound as a solid (yield 544 mg,32%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 4.23 (2H, s), 6.16 (1H,s), 7.23-7.49 (8H, m), 8.28 (1H, s).

Reference Example 78 tert-butylmethyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate

Under an argon atmosphere, a mixture of tert-butyl({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(100 mg), methylboronic acid (14 mg),tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90mg) and dioxane (3 mL) was stirred at 80° C. for 24 hr. Methylboronicacid (14 mg) and tetrakis(triphenylphosphine)palladium (25 mg) wereadded, and the mixture was stirred at 90° C. for 24 hr. Methylboronicacid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassiumcarbonate (90 mg) and dioxane (2 mL) were added, and the mixture wasstirred at 90° C. for 24 hr. The reaction mixture was diluted with ethylacetate, washed successively with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the titlecompound as an oil (yield 85.8 mg, 36%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.58 (3H, s), 2.81 (3H, s), 4.20-4.23(2H, m), 6.13 (1H, s), 7.07-7.10 (1H, m), 7.24-7.42 (7H, m), 8.39 (1H,s).

Reference Example 79 tert-butyl methyl{[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

Under an argon atmosphere, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(232 mg), 3-thienylboronic acid (138 mg),tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate(175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at105° C. for 1 hr. The reaction mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=1:1) to give the title compound as apale-yellow oil (yield 189 mg, 81%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, brs), 4.22 (2H, brs), 6.17(1H, brs), 7.04-7.06 (1H, m), 7.16-7.17 (1H, m), 7.25-7.32 (3H, m),7.57-7.61 (1H, m), 8.56 (1H, d, J=2.4 Hz), 8.71-8.73 (1H, m).

Reference Example 80 tert-butyl{[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-fluorophenyl)boronic acid (195 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 293 mg,94%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.12(1H, brs), 7.00-7.06 (2H, m), 7.18-7.31 (4H, m), 7.56-7.60 (1H, m),8.54-8.55 (1H, m), 8.73-8.75 (1H, m).

Reference Example 81 tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2-methylphenyl)boronic acid (190 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 210 mg,68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2-methylphenyl)boronic acid (190 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at105° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as apale-yellow oil (yield 210 mg, 68%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 4.26 (2H,brs), 6.07 (1H, d, J=1.2 Hz), 6.87-6.89 (1H, m), 7.09-7.19 (2H, m),7.26-7.35 (3H, m), 7.58-7.62 (1H, m), 8.54-8.55 (1H, m), 8.75-8.77 (1H,m).

Reference Example 82 tert-butyl{[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-fluoro-2-methylphenyl)boronic acid (215 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 216 mg,67%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 4.25 (2H,brs), 6.05 (1H, br), 6.79-6.91 (3H, m), 7.30-7.35 (2H, m), 7.61-7.65(1H, m), 8.58-8.59 (1H, m), 8.77-8.79 (1H, m).

Reference Example 83 tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-methyl-3-thienyl)boronic acid (198 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 200 mg,64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-methyl-3-thienyl)boronic acid (198 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at105° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as apale-yellow oil (yield 200 mg, 64%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.81 (3H, s), 2.83 (3H, brs), 4.26 (2H,brs), 6.10 (1H, br), 6.90 (1H, br), 7.02-7.03 (1H, m), 7.26-7.35 (2H,m), 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.75-8.77 (1H, m).

Reference Example 84 tert-butyl{[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (3-cyanophenyl)boronic acid (205 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 298 mg,94%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.21(1H, br), 7.31-7.35 (2H, m), 7.46-7.69 (6H, m), 8.56 (1H, d, J=1.8 Hz),8.76-8.78 (1H, m)

Reference Example 85 tert-butyl{[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2-chlorophenyl)boronic acid (218 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-blue oil (yield 171 mg,53%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.84 (3H, brs), 4.26 (2H, brs), 6.20(1H, d, J=1.8 Hz), 7.26-7.36 (6H, m), 7.65-7.71 (1H, m), 8.58-8.59 (1H,m), 8.75-8.79 (1H, m).

Reference Example 86 tert-butyl{[5-(2,4-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2,4-difluorophenyl)boronic acid (198 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 113 mg,50%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 6.49(1H, br), 6.78-6.92 (3H, m), 7.48-7.58 (1H, m), 8.78 (1H, br).

Reference Example 87 tert-butyl{[5-(2,5-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2,5-difluorophenyl)boronic acid (220 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 135 mg,60%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 6.56(1H, br), 6.77-6.85 (2H, m), 7.00-7.08 (1H, m), 7.20-7.26 (1H, m), 8.90(1H, br).

Reference Example 88 tert-butyl{[5-(4-chloro-2-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-chloro-2-fluorophenyl)boronic acid (243 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 127 mg,54%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, s), 4.30 (2H, s), 6.55 (1H,br), 6.80 (1H, br), 7.11-7.15 (2H, m), 7.46-7.52 (1H, m), 8.82 (1H, br).

Reference Example 89 tert-butyl{[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 44 and using tert-butyl{[5-(2,4-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (113 mg),sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 mL) andpyridine-3-ylsulfonyl chloride hydrochloride (113 mg), the titlecompound was obtained as a pale-yellow oil (yield 110 mg, 68%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, brs), 4.24 (2H, brs), 6.19(1H, br), 6.77-6.92 (2H, m), 7.11-7.19 (1H, m), 7.33-7.37 (2H, m),7.68-7.72 (1H, m), 8.62 (1H, d, J=2.4 Hz), 8.77-8.79 (1H, m).

Reference Example 90 tert-butyl{[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 44 and using tert-butyl{[5-(2,5-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (135 mg),sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (135 mg), the title compoundwas obtained as a colorless oil (yield 105 mg, 54%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.82 (3H, s), 4.23 (2H, brs), 6.24 (1H,br), 6.89-7.13 (4H, m), 7.33-7.39 (2H, m), 7.71-7.75 (1H, m), 8.67 (1H,d, J=2.4 Hz), 8.78-8.80 (1H, m).

Reference Example 91 tert-butyl{[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 44 and using tert-butyl{[5-(4-chloro-2-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (127mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0.22 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (120 mg), the title compoundwas obtained as a colorless oil (yield 103 mg, 57%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.81 (3H, s), 4.23 (2H, brs), 6.21 (1H,brs), 7.08-7.15 (4H, m), 7.32-7.38 (2H, m), 7.69-7.73 (1H, m), 8.64 (1H,d, J=2.4 Hz), 8.77-8.79 (1H, m).

Reference Example 92 tert-butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (3-fluorophenyl)boronic acid (195 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 280 mg,90%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.16(1H, brs), 6.93-7.11 (3H, m), 7.27-7.32 (3H, m), 7.59-7.63 (1H, m), 8.58(1H, d, J=2.1 Hz), 8.73-8.75 (1H, m).

Reference Example 93 tert-butyl{[5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

5-Bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (565mg) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), a 40%solution (1.5 mL) of methylamine methanol was added at room temperatureand the mixture was stirred for 30 min. Sodium borohydride (130 mg) wasadded to the reaction mixture at room temperature and the mixture wasstirred for 15 min. The reaction mixture was concentrated under reducedpressure, a saturated aqueous sodium hydrogencarbonate solution wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate (6 mL), di-tert-butyl bicarbonate(0.45 mL) was added, and the mixture was stirred at room temperature for1 hr. To the reaction mixture was added 1 mol/L hydrochloric acid (10mL), and the mixture was further stirred for 15 min. The reactionmixture was neutralized with saturated aqueous sodium hydrogencarbonatesolution, and extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to givea mixture of the title compound and5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde. Themixture was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution (4mL) of methylamine in tetrahydrofuran was added, and the mixture wasstirred at room temperature for 12 hr. To the reaction mixture was addeda solution of sodium borohydride (131 mg) in methanol (1 mL), and themixture was stirred for 1 hr. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (6 mL),di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture wasstirred at room temperature for 1 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=2:1) to give thetitle compound as a yellow oil (yield 384 mg, 50%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.49 (3H, s), 2.71 (3H, brs), 4.15 (2H,brs), 6.24 (1H, brs), 7.47-7.52 (1H, m), 8.13-8.17 (1H, m), 8.84-8.86(1H, m), 9.07-9.08 (1H, m).

Reference Example 94 2-bromo-1-(2,6-difluorophenyl)ethanone

To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethylether (50 mL) was added anhydrous aluminum chloride (86 mg) and themixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at10-15° C. After stirring at room temperature for 2 hr, the mixture waspoured into water, and the mixture was extracted with ethyl acetate. Theobtained organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, concentrated under reduced pressure to givethe title compound as a pale-yellow oil (yield 15.2 g, about 100%).

¹H-NMR (CDCl₃) δ: 4.37 (2H, s), 6.97-7.04 (2H, m), 7.43-7.53 (1H, m).

Reference Example 95 ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate

To a solution of ethyl cyanoacetate (7.24 g) and diisopropylethylamine(19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of2-bromo-1-(2,6-difluorophenyl)ethanone (15.16 g) in tetrahydrofuran (15mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr.The reaction mixture was filtered, and the obtained filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed successively with water, 1 mol/L hydrochloric acid andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to givethe title compound as a pale-green oil (yield 13.8 g, 81%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 3.44-3.53 (1H, m), 3.63-3.72(1H, m), 4.13-4.18 (1H, m), 4.31 (2H, q, J=7.1 Hz), 6.95-7.05 (2H, m),7.44-7.54 (1H, m).

Reference Example 96 methyl2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate

4-Cyclohexylacetophenone (10.0 g) was dissolved in chloroform (30 mL)and diethyl ether (30 mL), and bromine (8.70 g) was slowly addeddropwise. After completion of the dropwise addition, the reactionmixture was stirred at room temperature for 1 hr, diluted with water andextracted with chloroform. The extract was washed with water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive crude 2-bromo-1-(5-cyclohexylpyridin-2-yl)ethanone (15.8 g) as anoil. This was dissolved in tetrahydrofuran (20 mL), and added dropwiseto a mixture of methyl cyanoacetate (4.95 g), diisopropylethylamine(16.2 g) and tetrahydrofuran (50 mL). The reaction mixture was stirredat room temperature for 20 hr, the insoluble material was filtered off,and the filtrate was concentrated under reduced pressure. The residuewas dissolved in ethyl acetate, washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→3:1) to give the title compound as an oil(yield 12.1 g, 82%).

¹H-NMR (CDCl₃) δ: 1.20-1.51 (5H, m), 1.70-1.90 (5H, m), 2.51-2.64 (1H,m), 3.47-3.73 (1H, m), 3.58-3.88 (1H, m), 3.85 (3H, s), 4.09-4.19 (1H,m), 7.32 (2H, d, J=8.1 Hz), 7.89 (2H, d, J=8.1 Hz).

Reference Example 97 ethyl2-chloro-5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate

A solution (14 mL) of ethyl2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (13.83 g) in ethyl acetatewas added dropwise to 4 mol/L hydrogen chloride-ethyl acetate solution(100 mL) at 10-15° C. The mixture was stirred at room temperature for 12hr, and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→8:2)to give the title compound as yellow crystals (yield 10.0 g, 68%).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.2 Hz), 4.34 (2H, q, J=7.2 Hz),6.95-7.04 (2H, m), 7.14-7.23 (2H, m), 9.20 (1H, br).

Reference Example 98 methyl2-chloro-5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate

14% Hydrogen chloride-1,4-dioxane solution (50 mL) was added to methyl2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixturewas stirred at room temperature for 8 hr and concentrated under reducedpressure. The residue was dissolved in ethyl acetate, washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was crystallized fromdiisopropyl ether and collected by filtration to give a nearly 1:1mixture (3.41 g) of the title compound and methyl2-amino-5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=7:2) to give thetitle compound as crystals (yield 0.64 g, 5%).

¹H-NMR (CDCl₃) δ: 1.22-1.48 (5H, m), 1.71-1.91 (5H, m), 2.46-2.58 (1H,m), 3.86 (3H, s), 6.81 (1H, d, J=3.2 Hz), 7.23 (2H, d, J=8.3 Hz), 7.36(2H, d, J=8.3 Hz), 8.67 (1H, brs).

Reference Example 99 methyl2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate(4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide inthe same manner as in Reference Example 95 and Reference Example 97 inacetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate(6.26 g) over 10 min under ice-cooling. The reaction mixture was stirredat the same temperature for 2 hr and at room temperature for 2 hr, andconcentrated under reduced pressure. A saturated aqueous sodiumhydrogencarbonate solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→7:3) to give the title compound as a pale-yellow solid(yield 815 mg, 16%). More specifically, to a solution of methylcyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran(2600 mL) was added dropwise a solution of phenacyl bromide (75 g) intetrahydrofuran (370 mL). The mixture was stirred at room temperaturefor 12 hr. The reaction mixture was filtered, and the obtained filtratewas concentrated under reduced pressure. The residue was dissolved inethyl acetate, washed successively with 1 mol/L hydrochloric acid, waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was washed with diethylether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil(yield 77.4 g, 95%). To a solution (125 mL) of ethyl2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetatewas added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25mL). The mixture was stirred at room temperature for 18 hr, andconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with 6% aqueous sodium hydrogencarbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was washed with diisopropyl ether to givemethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals(yield 10.0 g, 37%). The title compound was synthesized from thethus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 7.26-7.32 (1H, m), 7.40-7.60 (4H, m),8.29 (1H, br).

Reference Example 100 ethyl5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate

To a solution of ethyl2-chloro-5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate (9.82 g) inethanol (200 mL) was added 10% palladium carbon (50% containing water,4.91 g), and the mixture was stirred under a hydrogen atmosphere at 40°C. for 72 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1) to give thetitle compound as colorless crystals (yield 3.80 g, 24%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.2 Hz), 4.32 (2H, q, J=7.2 Hz),6.94-7.04 (2H, m), 7.11-7.21 (1H, m), 7.24-7.27 (1H, m), 7.54-7.55 (1H,m) 9.37 (1H, br).

Reference Example 101 methyl5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate

To a solution of a nearly 1:1 mixture (3.41 g) of methyl2-chloro-5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate and methy2-amino-5-(4-cyclohexylphenyl)-3-furoate in methanol (30 mL) and ethylacetate (10 mL) was added 10% palladium carbon (50% containing water,0.34 g), and the mixture was stirred under a hydrogen atmosphere at 50°C. for 14 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=3:1→2:1) to givethe title compound as crystals (yield 1.25 g, 41%).

¹H-NMR (CDCl₃) δ: 1.19-1.50 (5H, m), 1.73-1.93 (5H, m), 2.43-2.57 (1H,m), 3.84 (3H, s), 6.86 (1H, s), 7.24 (2H, d, J=8.3 Hz), 7.41 (2H, d,J=8.3 Hz), 7.45 (1H, dd, J=3.0, 1.7 Hz), 8.73 (1H, brs).

Reference Example 102 methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

Methyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (0.92 mg),10% palladium carbon (50% containing water, 0.20 g) and triethylamine(0.56 mL) were suspended in methanol (30 mL), and the mixture wasstirred under a hydrogen atmosphere at room temperature for 2 hr. Thereaction mixture was filtered through celite, and the insoluble materialwas washed with ethyl acetate. The filtrate was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the titlecompound as a colorless solid (yield 0.69 g, 87%).

¹H-NMR (CDCl₃) δ: 3.87 (3H, s), 7.24-7.31 (2H, m), 7.39-7.46 (2H, m),7.51-7.54 (2H, m), 8.32 (1H, br).

Reference Example 103 [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol

A solution (35 mL) of ethyl5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate (3.35 g) intetrahydrofuran was cooled to −50° C., and a 1.5 mol/L solution (30 mL)of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The mixture was stirred at the same temperature for 1 hr,water was added to the reaction mixture, and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was diluted with ethylacetate, celite and anhydrous magnesium sulfate were added and themixture was further stirred for 15 min. The suspension was filtrated,and the obtained filtrate was concentrated under reduced pressure togive the title compound as pale-red crystals (yield 2.70 g, 97%).

¹H-NMR (CDCl₃) δ: 1.46 (1H, br), 4.64 (2H, s), 6.88-7.02 (4H, m),7.06-7.16 (1H, m), 9.07 (1H, br).

Reference Example 104 [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl]methanol

To a solution of methyl 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate(3.0 g) in absolute tetrahydrofuran (40 mL) was added dropwise a 1.5mol/L solution (21.0 mL) of diisobutylaluminum hydride in toluene at−78° C. The mixture was further stirred at the same temperature for 2hr. To the reaction mixture was added 1 mol/L hydrochloric acid, and themixture was diluted with ethyl acetate. The insoluble material wasfiltered off through celite, and the filtrate was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as crystals (yield1.07 g, 40%).

¹H-NMR (CDCl₃) δ: 1.16-1.50 (5H, m), 1.69-1.93 (5H, m), 2.45-2.55 (1H,m), 4.60 (2H, s), 6.45-6.51 (1H, m), 6.81-6.86 (1H, m), 7.21 (2H, d,J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 8.30 (1H, br), 1H not detected.

Reference Example 105 5-(2,6-difluorophenyl)-1H-pyrrole-3-carbaldehyde

To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol(2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate(430 mg), N-methylmorpholine N-oxide (2.15 g) and molecular sieves 4Apowder (5 g), and the mixture was stirred at room temperature for 2 hr.The reaction mixture was diluted with ethyl acetate (60 mL) and filteredthrough celite. The filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as pale-redcrystals (yield 1.94 g, 77%).

¹H-NMR (CDCl₃) δ: 6.97-7.06 (2H, m), 7.16-7.24 (1H, m), 7.28-7.31 (1H,m), 7.56-7.58 (1H, m), 9.55 (1H, br), 9.88 (1H, s).

Reference Example 106 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde

To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl]methanol(1.00 g) in acetonitrile were added tetra-n-propylammonium perruthenate(115 mg), N-methylmorpholine N-oxide (0.60 g) and molecular sieves 4Apowder (1.15 g) under ice-cooling. The mixture was stirred at roomtemperature for 1.5 hr, and the reaction mixture was suspended in ethylacetate, and filtered through celite. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=2:1) to give thetitle compound as crystals (yield 0.53 g, 53%).

¹H-NMR (CDCl₃) δ: 1.17-1.49 (5H, m), 1.70-1.95 (5H, m), 2.45-2.58 (1H,m), 6.89 (1H, s), 7.25 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.47(1H, s), 8.99 (1H, brs), 9.82 (1H, s).

Reference Example 107 1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (13.7 g) in tetrahydrofuran (450 mL)was added dropwise pyrrole (17.4 g) under ice-cooling. The reactionmixture was stirred at the same temperature for 1.5 hr, andtriisopropylsilyl chloride (50.0 g) was added dropwise at the sametemperature. The mixture was further stirred at below 10° C. for 1.5 hr,ice water was added and the mixture was extracted with diethyl ether.The extract was washed with water, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. A solution of the residue (57.7g) in dichloromethane (30 mL) was added at once to a suspension of(chloromethylene)dimethylammonium chloride (36.5 g) in dichloromethane(500 mL) at 0° C. The reaction mixture was refluxed for 30 min andcooled to 0° C. The resulting solid was collected by filtration, andwashed with diethyl ether. The obtained solid was dissolved in water (50mL), a 1 mol/L aqueous sodium hydroxide solution (500 mL) was added atroom temperature, and the mixture was stirred for 2 hr. The reactionmixture was extracted with chloroform and ethyl acetate. The extract wasdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was washed with diisopropyl ether to give thetitle compound as pale-brown crystals (yield 9.4 g, 38%).

¹H-NMR (CDCl₃) δ: 6.68-6.70 (1H, m), 6.83-6.86 (1H, m), 7.45-7.47 (1H,m), 9.00-9.20 (1H, m), 9.82 (1H, s)

Reference Example 108 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone

Magnesium (flake, 6.2 g) was suspended in diethyl ether (10 mL), andiodine (small amount) was added and a solution of 2-bromotoluene (43.26g) in diethyl ether (100 mL) were slowly added dropwise. After stirringat room temperature for 1 hr, the reaction mixture was added dropwise toa solution of chlorodifluoroacetic acid (10.0 g) in diethyl ether (100mL) at −10° C., and the mixture was stirred at 0° C. for 1 hr. Saturatedaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with diethyl ether. The extract was washedwith saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was distilled under reduced pressure(boiling point: 81-82° C./12-13 mmHg) to give the title compound as apale-yellow oil (yield 4.9 g, 31%).

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 7.29-7.36 (2H, m), 7.47-7.53 (1H, m),7.89-7.92 (1H, m).

Reference Example 109 2,2-difluoro-2-iodo-1-(2-methylphenyl)ethanone

To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were addedtrimethylsilyl chloride (3.1 mL) and2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone (4.0 g), and themixture was stirred at 55° C. for 3 hr. The reaction mixture was allowedto cool to room temperature, iodine (3.5 g) was added, and the mixturewas further stirred for 2 hr. Water was added to the reaction mixture,and the mixture was extracted with diethyl ether. The extract was washedwith aqueous sodium hydrogen sulfite solution, aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane) togive the title compound as a yellow oil (yield 2.6 g, 46%).

¹H-NMR (CDCl₃) δ: 2.51 (3H, s), 7.26-7.35 (2H, m), 7.46-7.51 (1H, m),7.91-7.94 (1H, m).

Reference Example 1102,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one

Under a nitrogen atmosphere, to a mixture oftetrakis(triphenylphosphine)palladium (0.52 g) and vinyltrimethylsilane(1.9 mL) was added 2,2-difluoro-2-iodo-1-(2-methylphenyl)ethanone (2.6g), and the mixture was stirred at room temperature for 2 hr. Diethylether was added to the reaction mixture, the insoluble material wasfiltered off, and the filtrate was concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent: hexane) to give the title compound as a colorless oil (yield2.6 g, 74%).

¹H-NMR (CDCl₃) δ: 0.21 (9H, s), 2.50 (3H, s), 2.70-2.89 (2H, m),3.19-3.24 (1H, m), 7.27-7.32 (2H, m), 7.42-7.48 (1H, m), 7.89-7.92 (1H,m).

Reference Example 111 3-fluoro-2-(2-methylphenyl)-1H-pyrrole

To a solution (20 mL) of2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one (2.5g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), andthe mixture was stirred at room temperature for 14 hr. The reactionmixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved inacetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g)was added. The reaction mixture was stirred at 60° C. for 3 hr, andconcentrated under reduced pressure. The residue was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1) to give the title compound as a pale-yellowoil (yield 0.87 g, 78%).

¹H-NMR (CDCl₃) δ: 2.39 (3H, d, J=1.5 Hz), 6.06-6.08 (1H, m), 6.60-6.63(1H, m), 7.19-7.33 (4H, m), 7.71 (1H, brs).

Reference Example 112 5-bromo-1H-pyrrole-3-carbaldehyde

A solution of 1H-pyrrole-3-carbaldehyde (19.1 g) in tetrahydrofuran (300mL) was cooled to −70° C., and a solution of N-bromosuccinimide (35.8 g)in N,N-dimethylformamide (100 mL) was added dropwise. After stirring atthe same temperature for 1 hr, the mixture was raised to −10° C. over 2hr and further stirred for 30 min. Ice water was added to the reactionmixture at 0° C., and the mixture was allowed to warm to roomtemperature and extracted with ethyl acetate. The extract was washedwith 10% aqueous citric acid solution, 6% aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The crystalsobtained as a residue were washed with diisopropyl ether to give thetitle compound as colorless crystals (yield 17.7 g, 51%).

¹H-NMR (CDCl₃) δ: 6.65-6.66 (1H, m), 7.37-7.38 (1H, m), 8.80 (1H, br),9.70 (1H, s).

Reference Example 113 5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde

5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2-methylphenylboronic acid(94 mg) and sodium carbonate (146 mg) were suspended in a mixed solventof 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture wassufficiently degassed under a nitrogen atmosphere.Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixturewas further degassed and refluxed at 105° C. for 24% hr. The reactionmixture was allowed to cool to room temperature, and the mixture wasextracted with water and ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the titlecompound as colorless crystals (yield 72 mg, 68%).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 6.75-6.77 (1H, m), 7.23-7.36 (4H, m),7.50-7.51 (1H, m), 8.75 (1H, br), 9.85 (1H, s).

Reference Example 1144-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

To a solution (15 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g)at 0° C., and the mixture was stirred at 60° C. for 2 hr. The mixturewas cooled to room temperature, water was added and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to givethe title compound as a yellow powder (yield 0.55 g, 46%).

¹H-NMR (CDCl₃) δ: 7.15-7.40 (3H, m), 7.52 (1H, d, J=3.6 Hz), 7.97-8.03(1H, m), 9.24 (1H, br), 9.96 (1H, s).

Reference Example 1154-fluoro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

To a solution (60 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(3.1 g) in tetrahydrofuran was added 2,6-dichloro-N-fluoropyridiniumtriflate (5.6 g) at 0° C., and the mixture was stirred at the sametemperature for 2 hr. Saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as whitecrystals (yield 0.43 g, 13%).

¹H-NMR (CDCl₃) δ: 7.11-7.30 (4H, m), 7.80-7.87 (1H, m), 9.14 (1H, brs),9.88 (1H, s).

Reference Example 1164-fluoro-5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (0.40 g) was washed twice with hexane and suspended intetrahydrofuran (10 mL). A solution of3-fluoro-2-(2-methylphenyl)-1H-pyrrole (0.86 g) in tetrahydrofuran (3mL) was added at 0° C., and the mixture was stirred at the sametemperature for 30 min. A solution (2 mL) of triisopropylsilyltrifluoroacetate (2.7 mL) in tetrahydrofuran was added at 0° C., and themixture was stirred at the same temperature for 15 min. Ice water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (10 mL) and acetonitrile (2mL), (chloromethylene)dimethylammonium chloride (1.6 g) was added, andthe mixture was heated under reflux for 2 hr, and concentrated underreduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), 1mol/L aqueous sodium hydroxide solution (20 mL) was added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as ayellow oil (yield 0.48 g, 48%).

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 7.23-7.32 (5H, m), 8.38 (1H, brs), 9.87(1H, s).

Reference Example 117 5-nitro-3-(trifluoromethyl)pyridin-2-ol

2-Hydroxy-3-(trifluoromethyl)pyridine (3.0 g) was added to conc.sulfuric acid (18 mL) under ice-cooling, and the mixture was stirred atthe same temperature for 5 min. Fuming nitric acid (90-95%, 7 mL) wasadded dropwise over 5 min, and the mixture was allowed to return to roomtemperature over 2 hr, heated to 50° C. and stirred for 3 hr. Aftercooling to room temperature, the reaction mixture was poured into ice(200 g), and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The precipitate was washed withdiisopropyl ether to give the title compound as a solid (yield 2.7 g,69%).

¹H-NMR (CDCl₃) δ: 8.65-8.67 (1H, m), 8.80-8.81 (1H, m), 1H not detected.

Reference Example 118 2-chloro-5-nitro-3-(trifluoromethyl)pyridine

A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g),phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL)was stirred at 90° C. for 3 hr. After cooling to room temperature, thereaction mixture was poured into ice, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) to give the title compound as a yellowoil (yield 2.21 g, 77%).

¹H-NMR (CDCl₃) δ: 8.79-8.81 (1H, m), 9.40-9.41 (1H, m).

Reference Example 119 6-chloro-5-(trifluoromethyl)pyridine-3-amine

Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water(40 mL), and the mixture was stirred at room temperature for 5 min. Asolution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) inmethanol (40 mL) was added, and the mixture was stirred at roomtemperature for 1 hr. Reduced iron (2.3 g) was added, and the mixturewas further stirred at the same temperature for 3 hr. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was extracted with ethyl acetate, and the extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1)to give the title compound as a solid (yield 1.0 g, 65%).

¹H-NMR (CDCl₃) δ: 7.29 (1H, m), 7.99 (1H, m), 2H not detected.

Reference Example 120 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonylchloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20min to water (27 mL). The mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Separately,6-chloro-5-(trifluoromethyl)pyridine-3-amine (1.14 g) was added toconcentrated hydrochloric acid (9 mL) with stirring under ice-cooling,and concentrated hydrochloric acid (9 mL) was further added. A solutionof sodium nitrite (0.44 g) in water (6 mL) was added dropwise over 10min. The reaction mixture was gradually added at 5° C. to theabove-mentioned sulfur dioxide-containing solution added with cuprouschloride (15 mg). Under ice-cooling, the mixture was further stirred for30 min, and the precipitate was collected by filtration and washed withwater. The obtained precipitate was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the titlecompound as an orange solid (yield 437 mg, 27%).

¹H-NMR (CDCl₃) δ: 8.58 (1H, m), 9.18 (1H, m).

Reference Example 121 6-chloro-2-methylpyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water(24 mL) over 20 min. The mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Separately, to theconcentrated hydrochloric acid (6 mL) was added5-amino-2-chloro-6-methylpyridine (1.0 g) with stirring underice-cooling, and a solution of sodium nitrite (0.5 g) in water (2 mL)was added dropwise over 10 min. The reaction mixture was gradually addedat 5° C. to the above-mentioned sulfur dioxide-containing solution addedwith cuprous chloride (10 mg). Under ice-cooling, the mixture wasfurther stirred for 30 min, and the precipitate was collected byfiltration, and washed with water to give the title compound as apale-yellow solid (yield 1.1 g, 67%).

¹H-NMR (CDCl₃) δ: 2.99 (3H, s), 7.41 (1H, dd, J=8.7, 0.9 Hz), 8.26 (1H,d, J=8.4 Hz).

Reference Example 122 ethyl1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

By a similar reaction as in Reference Example 40 and using5-bromo-6-chloropyridine-3-sulfonyl chloride (3.49 g), the titlecompound was obtained as a yellow solid (yield 1.63 g, 38%).

¹H-NMR (CDCl₃) δ: 1.35-1.39 (3H, m), 4.29-4.37 (2H, m), 6.60 (1H, s),7.18-7.20 (2H, m), 7.35-7.51 (4H, m), 8.06 (1H, s), 8.45 (1H, s), 8.78(1H, s).

Reference Example 123 ethyl5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carboxylate

By a similar reaction as in Reference Example 40 and using6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (413 mg), thetitle compound was obtained as a colorless solid (yield 191 mg, 35%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.2 Hz), 4.33 (2H, dd, J=14.4, 7.2 Hz),6.61 (1H, s), 7.16-7.18 (2H, m), 7.33-7.45 (3H, m), 7.65 (1H, s), 8.09(1H, s), 8.75 (1H, s), 8.98 (1H, s).

Reference Example 124 ethyl1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

By a similar reaction as in Reference Example 40 and using6-chloro-2-methylpyridine-3-sulfonyl chloride (543 mg), the titlecompound was obtained as a red oil (yield 135 mg, 18%).

¹H-NMR (CDCl₃) δ: 1.35-1.40 (3H, m), 2.47 (3H, s), 4.33 (2H, dd, J=14.1,6.9 Hz), 6.59 (1H, d, J=1.8 Hz), 6.82-7.49 (7H, m), 8.21 (1H, d, J=2.1Hz), 8.51 (1H, dd, J=4.8, 1.8 Hz).

Reference Example 125 methyl4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

By a similar reaction as in Reference Example 36 and using methyl4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg), the title compoundwas obtained as a colorless solid (yield 206 mg, 73%). Morespecifically, to a solution of methyl4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg) in tetrahydrofuran(10 mL) was added sodium hydride (60% in oil, 94 mg), and the mixturewas stirred for 15 min. 15-Crown-5 (0.48 mL) was added, and the mixturewas further stirred for 15 min. Pyridine-3-sulfonyl chloridehydrochloride (219 mg) was added and the mixture was stirred for 30 min.Water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as a colorlesssolid (yield 206 mg, 73%).

¹H-NMR (CDCl₃) δ: 3.89 (3H, s), 7.17-7.20 (2H, m), 7.26-7.55 (5H, m),7.95 (1H, d, J=4.8 Hz), 8.50-8.51 (1H, m), 8.76-8.78 (1H, m).

Reference Example 1261-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 62 and using ethyl1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(1.63 g), the title compound was obtained as a pale-yellow solid (yield1.18 g, 80%).

¹H-NMR (CDCl₃) δ: 6.63 (1H, s), 7.17-7.20 (2H, m), 7.36-7.39 (2H, m),7.50-7.52 (2H, m), 8.10 (1H, s), 8.46 (1H, s), 8.79-8.80 (1H, m), 9.91(1H, s).

Reference Example 1275-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 62 and using ethyl5-phenyl-1-{[(5-trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carboxylate(190 mg), the title compound was obtained as a colorless solid (yield138 mg, 83%).

¹H-NMR (CDCl₃) δ: 6.64 (1H, d, J=1.5 Hz), 7.15-7.18 (2H, m), 7.33-7.38(2H, m), 7.44-7.47 (1H, m), 7.63-7.64 (1H, m), 8.14 (1H, d, J=1.5 Hz),8.76 (1H, d, J=2.1 Hz), 9.00 (1H, d, J=1.5 Hz), 9.92 (1H, s).

Reference Example 1281-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 62 and using ethyl1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(364 mg), the title compound was obtained as an orange solid (yield 182mg, 57%).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 6.62 (1H, d, J=1.8 Hz), 6.83-6.90 (1H,m), 7.02-7.04 (2H, m), 7.16-7.31 (3H, m), 7.39-7.42 (1H, m), 8.24 (1H,s), 8.52-8.54 (1H, m), 9.93 (1H, s).

Reference Example 1294-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Under a nitrogen atmosphere, a solution of methyl4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (200mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/Lsolution (1.85 mL) of diisobutylaluminum hydride in toluene was addedwith stirring. After stirring at the same temperature for 15 min, themixture was raised to 0° C. over 1.5 hr. Water (20 mL) was added, andthe mixture was stirred at the same temperature for 5 min. Afterstirring, ethyl acetate (20 mL) was added, and the mixture was stirredfor 15 min, and then stirred at room temperature for 20 min. Thereaction mixture was filtered through celite, and celite was washed withethyl acetate. The filtrate was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), manganese dioxide (75% chemicallytreated product, 1.0 g) was added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was filtered through celite,and celite was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:2) to give the titlecompound as a colorless solid (yield 123 mg, 67%).

¹H-NMR (CDCl₃) δ: 7.17-7.20 (2H, m), 7.26-7.57 (5H, m), 7.96 (1H, d,J=4.8 Hz), 8.50-8.51 (1H, m), 8.76-8.80 (1H, m), 9.92 (1H, s).

Reference Example 1305-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2,6-difluorophenyl)-1H-pyrrole-3-carbaldehyde (420mg) in tetrahydrofuran (42 mL) was added sodium hydride (60% in oil, 244mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (1.34 g) was added dropwise and the mixture was stirred for30 min. 3-Pyridylsulfonyl chloride hydrochloride (565 mg) was added, andthe mixture was further stirred for 1 hr. The reaction mixture wasdiluted with saturated brine, and the mixture was extracted with ethylacetate. The obtained extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=7:3→1:1), and crystallized fromdiisopropyl ether to give the title compound as colorless crystals(yield 590 mg, 84%).

¹H-NMR (CDCl₃) δ: 6.76 (1H, d, J=1.9 Hz), 6.90-6.95 (2H, m), 7.40-7.52(2H, m), 7.77-7.81 (1H, m), 8.18 (1H, d, J=1.9 Hz), 8.65-8.66 (1H, m),8.85-8.87 (1H, m), 9.91 (1H, s).

Reference Example 1315-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (60% in oil, 68 mg) was added to a solution of5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde (0.17 g) intetrahydrofuran (12 mL) at room temperature. The mixture was stirred for20 min, 3-pyridinesulfonyl chloride (0.19 g) was added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture waspoured into ice water, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=3:2→2:1) to give the title compound as crystals (yield 0.26 g,97%).

¹H-NMR (CDCl₃) δ: 1.21-1.53 (5H, m), 1.73-1.98 (5H, m), 2.50-2.60 (1H,m), 6.57 (1H, d, J=1.9 Hz), 7.03-7.09 (2H, m), 7.13-7.29 (3H, m), 7.48(1H, ddd, J=8.3, 2.0, 1.9 Hz), 8.11 (1H, d, J=1.9 Hz), 8.49 (1H, d,J=2.3 Hz), 8.73 (1H, dd, J=4.8, 1.6 Hz), 9.89 (1H, s).

Reference Example 1321-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 65 and using5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound wasobtained as a pale-red solid (yield 1.14 g, 66%). More specifically,5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved intetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(1.1 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g)was added. The reaction mixture was stirred at room temperature for 15min. Water was added, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-redsolid (yield 1.14 g, 66%).

¹H-NMR (CDCl₃) δ: 6.71 (1H, d, J=9.0 Hz), 7.05 (1H, t, J=9.0 Hz),7.19-7.23 (2H, m), 7.38 (1H, d, J=8.4 Hz), 7.45-7.53 (1H, m), 7.63-7.67(1H, m), 8.11 (1H, d, J=1.8 Hz), 8.33 (1H, d, J=2.7 Hz), 9.91 (1H, s).

Reference Example 1335-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, a mixture of1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(365 mg), methylboronic acid (90 mg),tetrakis(triphenylphosphine)palladium (116 mg), potassium carbonate (691mg) and 1,4-dioxane (25 mL) was stirred at 80° C. for 3 days. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→1:1) to give the title compound as a yellow solid (yield134 mg, 39%).

¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.04 (1H, t,J=8.4 Hz), 7.17-7.21 (3H, m), 7.45-7.50 (1H, m), 7.58 (1H, dd, J=8.7,3.6 Hz), 8.12 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4 Hz), 9.89 (1H, s).

Reference Example 1345-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar reaction as in Reference Example 65 and using5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (190 mg) andpyridine-2-sulfonyl chloride (231 mg), the title compound was obtainedas a pale-red solid (yield 183 mg, 55%).

¹H-NMR (CDCl₃) δ: 6.67 (1H, d, J=1.8 Hz), 6.97 (1H, t, J=8.7 Hz),7.07-7.10 (2H, m), 7.36-7.42 (1H, m), 7.52-7.55 (2H, m), 7.76-7.82 (1H,m), 8.23 (1H, d, J=1.5 Hz), 8.67 (1H, d, J=4.5 Hz), 9.92 (1H, s).

Reference Example 1355-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 65 and using5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (189 mg) and1-methyl-1H-pyrazole-4-sulfonyl chloride (217 mg), the title compoundwas obtained as yellow crystals (yield 217 mg, 65%).

¹H-NMR (CDCl₃) δ: 3.85 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.04-7.11 (1H,m), 7.17-7.22 (1H, m), 7.25-7.35 (3H, m), 7.43-7.50 (1H, m), 8.06 (1H,d, J=1.5 Hz), 9.86 (1H, s).

Reference Example 1365-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde (371 mg)in tetrahydrofuran (10 mL) were added sodium hydride (60% in oil, 288mg) and 15-crown-5 (1.32 g) at room temperature. After stirring for 5min, a suspension of pyridine-3-sulfonyl chloride hydrochloride (642 mg)in N,N-dimethylformamide (5 mL) was added at the same temperature. Afterstirring for 15 min, ice water was added, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as a red oil(yield 521 mg, 80%).

¹H-NMR (CDCl₃) δ: 1.82 (3H, s), 6.56 (1H, d, J=1.5 Hz), 6.87-6.90 (1H,m), 7.11-7.19 (2H, m), 7.30-7.39 (2H, m), 7.56-7.60 (1H, m), 8.15 (1H,d, J=1.5 Hz), 8.52-8.53 (1H, m), 8.80-8.82 (1H, m), 9.92 (1H, s).

Reference Example 1374-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

A suspension of sodium hydride (60% in oil, 216 mg) in tetrahydrofuran(5 mL) was cooled to 0° C., a solution of4-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (335 mg) intetrahydrofuran (5 mL), 15-crown-5 (991 mg), and pyridine-3-sulfonylchloride hydrochloride (482 mg) were added at 10° C. or below. Afterstirring for 15 min, water was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as a yellowpowder (yield 429 mg, 78%).

¹H-NMR (CDCl₃) δ: 7.02-7.08 (1H, m), 7.19-7.29 (2H, m), 7.37-7.41 (1H,m), 7.50-7.57 (1H, m), 7.68-7.72 (1H, m), 8.15 (1H, s), 8.54-8.55 (1H,m), 8.83-8.86 (1H, m), 9.97 (1H, s).

Reference Example 1384-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (60% in oil, 0.25 g) was washed twice with hexane andsuspended in tetrahydrofuran (10 mL). A solution (5 mL) of4-fluoro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.43 g) intetrahydrofuran was added at 0° C., and the mixture was stirred at thesame temperature for 30 min. 15-Crown-5 (1.3 mL) and 3-pyridinesulfonylchloride hydrochloride (0.68 g) were added at 0° C., and the mixture wasstirred at the same temperature for 1 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=1:1) to give the title compound as pale-yellow crystals (yield0.55 g, 76%).

¹H-NMR (CDCl₃) δ: 7.02-7.08 (1H, m), 7.20-7.31 (2H, m), 7.36-7.41 (1H,m), 7.48-7.55 (1H, m), 7.67-7.71 (1H, m), 8.00 (1H, d, J=5.1 Hz),8.55-8.56 (1H, m), 8.83-8.85 (1H, m), 9.93 (1H, s).

Reference Example 1394-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (60% in oil, 0.11 g) was washed twice with hexane andsuspended in tetrahydrofuran (10 mL). A solution (5 mL) of4-fluoro-5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde (0.45 g) intetrahydrofuran was added at 0° C., and the mixture was stirred at thesame temperature for 15 min. A solution (2 mL) of 15-crown-5 (0.56 mL)and 3-pyridinesulfonyl chloride (0.44 g) in tetrahydrofuran was added at0° C., and the mixture was stirred at the same temperature for 30 min.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as pale-yellowcrystals (yield 0.59 g, 77%).

¹H-NMR (CDCl₃) δ: 1.77 (3H, s), 7.02-7.04 (1H, m), 7.17-7.23 (2H, m),7.29-7.34 (1H, m), 7.37-7.42 (1H, m), 7.54-7.58 (1H, m), 8.00 (1H, d,J=4.5 Hz), 8.49-8.50 (1H, m), 8.81-8.83 (1H, m), 9.92 (1H, s).

Reference Example 1402-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(250 mg) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (10 mL)was added N-chlorosuccinimide (1.06 g) and the mixture was stirred for15 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution and saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as apale-yellow oil (yield 160 mg, 58%).

¹H-NMR (CDCl₃) δ: 6.74 (1H, s), 7.00-7.05 (2H, m), 7.42-7.56% (2H, m),8.10-8.14 (1H, m), 8.91 (1H, dd, J=4.9, 1.5 Hz), 9.07 (1H, d, J=2.1 Hz),9.92 (1H, s).

Reference Example 1412-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(331 mg) in N,N-dimethylformamide (33 mL) was added N-chlorosuccinimide(268 mg) and the mixture was stirred at 60° C. for 1 hr. A saturatedaqueous sodium hydrogencarbonate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1)to give the title compound as a colorless oil (yield 250 mg, 68%).

¹H-NMR (CDCl₃) δ: 6.65 (1H, s), 7.13-7.35 (3H, m), 7.45-7.55 (2H, m),8.09-8.13 (1H, m), 8.90-9.03 (2H, m), 9.92 (1H, s).

Reference Example 142 tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

1-[(5-Bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(1.18 g) was dissolved in absolute tetrahydrofuran (15 mL), a 2 mol/Lsolution (4.6 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas added to a solution of sodium borohydride (341 mg) in methanol (6mL), and the mixture was stirred at the same temperature for 5 min.di-tert-Butyl bicarbonate (3.87 g) was added, and water (15 mL) andsodium hydrogencarbonate (1.26 g) were added 5 min later. The mixturewas further stirred at room temperature for 30 min, water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→1:1), and fractions showing Rf values of 0.63, 0.30 and0.075 (eluent: hexane-ethyl acetate=3:1) by TLC analysis were collectedand concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), manganese dioxide (75% chemically treatedproduct, 3.0 g) was added, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was filtered through celite,and celite was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to givethe title compound as a colorless oil (yield 733 mg, 48%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 4.23 (2H, m), 6.16 (1H,s), 7.21-7.56 (7H, m), 8.44 (1H, s), 8.76 (1H, s).

Reference Example 143 tert-butyl{[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2,4-dimethylphenyl)boronic acid (209 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 177 mg,56%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.89 (3H, s), 2.36 (3H, s), 2.83 (3H,s), 4.25 (2H, brs), 6.03-6.04 (1H, m), 6.76 (1H, d, J=8.1 Hz), 6.92-6.95(1H, m), 7.00 (1H, brs), 7.26-7.33 (2H, m), 7.61-7.65 (1H, m), 8.56-8.57(1H, m), 8.75-8.77 (1H, m).

Reference Example 144 tert-butyl{[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg) was dissolved in toluene (10 mL), and the mixture wassufficiently degassed.Dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (66 mg) andtris(dibenzylideneacetone)dipalladium (0) (37 mg) were added at roomtemperature. The mixture was stirred for 30 min with deaeration, and a 2mol/L aqueous sodium carbonate solution (1.2 mL) and(2-formylphenyl)boronic acid (180 mg) were added. After further stirringat room temperature for 15 min, the mixture was heated to 120° C. over 1hr, and further stirred for 16 hr. The reaction mixture was cooled toroom temperature, water was added and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the title compound as a yellow oil(yield 218 mg, 48%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.86 (3H, s), 4.27 (2H, brs), 6.23 (1H,brs), 7.09-7.11 (1H, m), 7.28-7.33 (1H, m), 7.43 (1H, d, J=1.2 Hz),7.53-7.61 (3H, m), 7.96-7.99 (1H, m), 8.49-8.50 (1H, m), 8.75-8.77 (1H,m), 9.61-9.62 (1H, m).

Reference Example 145 tert-butyl methyl{[5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

A mixture of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg),tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under anitrogen atmosphere at 80° C. for 14 hr. The reaction mixture wasallowed to cool to room temperature, filtered through celite, and thefiltrate was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to givethe title compound as an oil (yield 275 mg, 64%).

¹H-NMR (CDCl₃) δ: 1.26 (9H, s), 2.79 (3H, s), 3.13 (3H, s), 4.22 (2H,s), 6.26 (1H, s), 7.26-7.37 (2H, m), 7.44-7.71 (3H, m), 7.93 (2H, d,J=8.3 Hz), 8.58 (1H, d, J=2.1 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz).

Reference Example 146 tert-butyl({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

tert-Butyl{[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(218 mg) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride(24 mg) and methanol (1 mL) were added at 0° C. After stirring at thesame temperature for 30 min, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1→1:3) to give the titlecompound as a colorless oil (yield 132 mg, 60%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.10-2.15 (1H, m), 2.85 (3H, s), 4.25(2H, brs), 4.30-4.38 (2H, m), 6.12 (1H, d, J=1.5 Hz), 6.69-6.72 (1H, m),7.13-7.18 (1H, m), 7.30-7.35 (2H, m), 7.44-7.49 (1H, m), 7.59-7.62 (2H,m), 8.50 (1H, d, J=2.4 Hz), 8.76-8.78 (1H, m).

Reference Example 147 5-mesityl-1H-pyrrole-3-carbaldehyde

A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g),2,4,6-trimethylphenylboronic acid (3.28 g), cesium carbonate (13.0 g),tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium(0) (0.23 g) and mesitylene (200 mL) was stirred with heating underreflux for 5 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=3:1) to give the titlecompound as a brown amorphous form (yield 0.30 g, 28%).

¹H-NMR (CDCl₃) δ: 2.11 (6H, s), 2.32 (3H, s), 6.51-6.52 (1H, m), 6.93(2H, s), 7.47-7.49 (1H, m), 9.82 (1H, s), 1H not detected.

Reference Example 148 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde

5-Bromo-1H-pyrrole-3-carbaldehyde (174 mg),[2-(methylthio)phenyl]boronic acid (202 mg) and sodium carbonate (254mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) andwater (2 mL), and the mixture was sufficiently degassed under a nitrogenatmosphere. Tetrakis(triphenylphosphine)palladium (58 mg) was added, andthe mixture was further degassed and stirred at 105° C. for 16 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to givethe title compound as pale-yellow crystals (yield 150 mg, 69%).

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 6.94-6.95 (1H, m), 7.21-7.31 (2H, m),7.39-7.42 (1H, m), 7.48-7.53 (2H, m), 9.85 (1H, s), 9.95 (1H, br).

Reference Example 149 5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 148 and using5-bromo-1H-pyrrole-3-carbaldehyde (870 mg), (2-bromophenyl)boronic acid(1.20 g), sodium carbonate (1.27 g) andtetrakis(triphenylphosphine)palladium (289 mg), the title compound wasobtained as colorless crystals (yield 396 mg, 32%).

¹H-NMR (CDCl₃) δ: 6.94-6.95 (1H, m), 7.16-7.22 (1H, m), 7.34-7.39 (1H,m), 7.49-7.54 (2H, m), 7.63-7.66 (1H, m), 9.28 (1H, br), 9.85 (1H, s).

Reference Example 1505-[2-(methylsulfinyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (200mg) in ethyl acetate (10 mL) was added 3-chloroperbenzoic acid (238 mg)under ice-cooling. After stirring at room temperature for 1 hr, asaturated sodium thiosulfate aqueous solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethyl acetate) to give thetitle compound as a pale-pink powder (yield 160 mg, 75%).

¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 7.04-7.06 (1H, m), 7.35-7.41 (1H, m),7.57-7.64 (2H, m), 7.72-7.82 (2H, m), 9.86 (1H, s), 12.35 (1H, br).

Reference Example 1515-[2-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (100mg) in ethyl acetate (5 mL) was added 3-chloroperbenzoic acid (318 mg)under ice-cooling. After stirring at room temperature for 3 hr, asaturated sodium thiosulfate aqueous solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:3)to give the title compound as pale-yellow crystals (yield 88.9 mg, 78%).

¹H-NMR (CDCl₃) δ: 2.77 (3H, s), 6.94-6.96 (1H, m), 7.54-7.60 (2H, m),7.67-7.73 (2H, m), 8.20-8.24 (1H, m), 9.88 (1H, s), 10.60 (1H, s).

Reference Example 1525-(2-fluorophenyl)-4-iodo-1H-pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved inN,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added andthe mixture was stirred at for 12 hr. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The extractwas washed successively with a saturated aqueous sodiumhydrogencarbonate solution, a 3% aqueous potassium hydrogensulfatesolution and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to givethe title compound as a pale-brown powder (yield 450 mg, 14%).

¹H-NMR (CDCl₃) δ: 7.16-7.30 (2H, m), 7.37-7.44 (1H, m), 7.63 (1H, d,J=3.4 Hz), 7.81-7.86 (1H, m), 9.24 (1H, br), 9.81 (1H, s).

Reference Example 1535-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-mesityl-1H-pyrrole-3-carbaldehyde (0.36 g) intetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.14 g)under ice-cooling, and the mixture was stirred at room temperature for0.5 hr. A solution of 15-crown-5 (0.75 g) in tetrahydrofuran (3 mL) wasadded and, after stirring for 5 min, pyridin-3-ylsulfonyl chloride (0.45g) was added under ice-cooling. The reaction mixture was stirred at roomtemperature for 0.5 hr, a saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=10:1→2:1) to give the titlecompound as a pale-brown amorphous form (yield 0.38 g, 62%).

¹H-NMR (CDCl₃) δ: 1.63 (6H, s), 2.35 (3H, s), 6.48 (1H, d, J=1.5 Hz),6.83 (2H, s), 7.26-7.35 (1H, m), 7.60-7.64 (1H, m), 8.17 (1H, dd, J=1.5,0.9 Hz), 8.56 (1H, d, J=2.1 Hz), 8.83 (1H, dd, J=4.5, 1.5 Hz), 9.90 (1H,s).

Reference Example 1545-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran(3 mL) were added a solution of5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (150 mg) intetrahydrofuran (5 mL), 15-crown-5 (182 mg) and pyridin-3-ylsulfonylchloride (135 mg) under ice-cooling. After stirring at room temperaturefor 2 hr, water was added and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as colorlesscrystals (yield 170 mg, 69%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 6.68 (1H, d, J=2.1 Hz), 6.97-6.99 (1H,m), 7.17-7.31 (3H, m), 7.40-7.45 (1H, m), 7.65-7.70 (1H, m), 8.16 (1H,d, J=2.1 Hz), 8.45-8.46 (1H, m), 8.75-8.77 (1H, m), 9.90 (1H, s).

Reference Example 1555-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 154 and using sodiumhydride (60% in oil, 91.0 mg),5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418mg) and pyridin-3-ylsulfonyl chloride (309 mg), the title compound wasobtained as a pale-yellow solid (yield 560 mg, 91%).

¹H-NMR (CDCl₃) δ: 6.66 (1H, d, J=1.5 Hz), 7.31-7.40 (4H, m), 7.48-7.52(1H, m), 7.66-7.71 (1H, m), 8.15 (1H, d, J=1.8 Hz), 8.55 (1H, d, J=2.7Hz), 8.82-8.84 (1H, m), 9.92 (1H, s).

Reference Example 1565-[2-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 154 and using sodiumhydride (60% in oil, 40 mg),5-[2-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbaldehyde (88.9 mg),15-crown-5 (94.4 mg) and pyridin-3-ylsulfonyl chloride (69.7 mg), thetitle compound was obtained as a colorless amorphous form (yield 72.0mg, 52%).

¹H-NMR (CDCl₃) δ: 2.87 (3H, s), 6.67 (1H, d, J=1.8 Hz), 7.37-7.48 (2H,m), 7.72-7.76 (3H, m), 8.02-8.05 (1H, m), 8.14 (1H, d, J=1.8 Hz), 8.50(1H, d, J=2.7 Hz), 8.81-8.83 (1H, m), 9.89 (1H, s).

Reference Example 1572-[4-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl]benzonitrile

A suspension of5-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(102 mg), zinc cyanide (61.0 mg) andtetrakis(triphenylphosphine)palladium (60.0 mg) in N,N-dimethylformamide(2 mL) was heated (100 W, 4 min 30 sec) using a microwave focusedchemical synthesis reactor manufactured by CEM, water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield97.4 mg, 63%).

¹H-NMR (CDCl₃) δ: 6.79 (1H, d, J=1.8 Hz), 7.41-7.51 (2H, m), 7.58-7.78(4H, m), 8.17 (1H, d, J=1.5 Hz), 8.45 (1H, d, J=2.7 Hz), 8.84-8.86 (1H,m), 9.91 (1H, s).

Reference Example 1585-(2-fluorophenyl)-4-iodo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (42 mL) of5-(2-fluorophenyl)-4-iodo-1H-pyrrole-3-carbaldehyde (400 mg) intetrahydrofuran was added sodium hydride (60% in oil, 102 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (560 mg)was added dropwise and the mixture was stirred for 30 min.Pyridin-3-ylsulfonyl chloride (340 mg) was added, and the mixture wasfurther stirred for 1 hr. The reaction mixture was diluted withsaturated brine and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=3:2→1:1) and crystallized from diisopropyl ether to give thetitle compound as colorless crystals (yield 540 mg, 93%).

¹H-NMR (CDCl₃) δ: 7.01-7.07 (1H, m), 7.12-7.17 (1H, m), 7.23-7.28 (1H,m), 7.37-7.41 (1H, m), 7.50-7.58 (1H, m), 7.69-7.73 (1H, m), 8.21 (1H,s), 8.54-8.54 (1H, m), 8.85 (1H, dd, J=4.9, 1.5 Hz), 9.85 (1H, s).

Reference Example 1595-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g),2,6-dimethylphenylboronic acid (4.50 g), cesium carbonate (13.0 g),tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium(0) (0.23 g) and mesitylene (200 mL) was stirred with heating underreflux for 5 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=3:1) to give a brown oil(0.48 g). To a solution of the oil in tetrahydrofuran (20 mL) was addedsodium hydride (60% in oil, 0.19 g) under ice-cooling, and the mixturewas stirred at room temperature for 0.5 hr. A solution of 15-crown-5(1.06 g) in tetrahydrofuran (3 mL) was added, and the mixture wasstirred for 5 min. Pyridin-3-ylsulfonyl chloride (0.64 g) was addedunder ice-cooling. The reaction mixture was stirred at room temperaturefor 0.5 hr, a saturated aqueous sodium hydrogencarbonate solution wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=2:1) to give thetitle compound as a pale-brown oil (yield 0.42 g, 25%).

¹H-NMR (CDCl₃) δ: 1.66 (6H, s), 6.52 (1H, d, J=2.1 Hz), 6.70 (2H, d,J=7.5 Hz), 7.25-7.34 (2H, m), 7.56-7.60 (1H, m), 8.19 (1H, d, J=1.5 Hz),8.53 (1H, d, J=1.8 Hz), 8.81-8.83 (1H, m), 9.91 (1H, s).

Reference Example 1602-bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(330 mg) was dissolved in N,N-dimethylformamide (30 mL),N-bromosuccinimide (356 mg) was added and the mixture was stirred at 80°C. for 2 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=7:3) and crystallized fromdiisopropyl ether to give the title compound as colorless crystals(yield 270 mg, 66%).

¹H-NMR (CDCl₃) δ: 6.70 (1H, s), 7.12-7.26 (2H, m), 7.29-7.35 (1H, m),7.44-7.52 (2H, m), 8.07-8.11 (1H, m), 8.89 (1H, dd, J=4.9, 1.5 Hz),9.01-9.02 (1H, m), 9.86 (1H, s).

Reference Example 1612-(2-fluorophenyl)-4-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile

5-(2-Fluorophenyl)-4-iodo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(489 mg), copper (I) cyanide (480 mg),tris(dibenzylideneacetone)dipalladium (0) (49 mg) and1,1′-bis(diphenylphosphino)ferrocene (89 mg) were mixed in 1,4-dioxane(20 mL), and the mixture was heated under reflux for 3 hr. The reactionmixture was allowed to cool, diluted with ethyl acetate, and filtered.The obtained filtrate was washed with a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=2:3→3:7) to give the title compound as a colorless oil (yield380 mg, about 100%).

¹H-NMR (CDCl₃) δ: 7.06-7.12 (1H, m), 7.24-7.32 (2H, m), 7.40-7.45 (1H,m), 7.55-7.63 (1H, m), 7.70-7.74 (1H, m), 8.19 (1H, s), 8.57 (1H, d,J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.6 Hz), 9.97 (1H, s).

Reference Example 1625-(2-fluorophenyl)-3-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-carbonitrile

2-Bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(340 mg), copper (I) cyanide (400 mg),tris(dibenzylideneacetone)dipalladium (0) (40 mg),1,1′-bis(diphenylphosphino)ferrocene (70 mg) were mixed in 1,4-dioxane(30 mL), and the mixture was heated under reflux for 24 hr. The reactionmixture was allowed to cool, diluted with ethyl acetate, and filtered.The obtained filtrate was washed with a saturated aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=3:2) and crystallized from diisopropyl ether to give the titlecompound as colorless crystals (yield 169 mg, 57%).

¹H-NMR (CDCl₃) δ: 6.72 (1H, s), 7.12-7.18 (1H, m), 7.24-7.28 (2H, m),7.50-7.60 (2H, m), 8.10-8.14 (1H, m), 8.82 (1H, d, J=2.4 Hz), 8.92 (1H,dd, J=4.9, 1.5 Hz), 10.09 (1H, s).

Reference Example 163 tert-butyl({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

Sodium hydride (60% in oil, 433 mg) was washed twice with hexane, andsuspended in tetrahydrofuran (20 mL). A solution of tert-butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (2.66 g) intetrahydrofuran (10 mL) was added to the suspension at 0° C., and asolution of 15-crown-5 (2.20 mL) and 6-methoxypyridin-3-ylsulfonylchloride (2.29 g) in tetrahydrofuran (5 mL) was added at the sametemperature. After stirring at room temperature for 30 min, water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=6:1) to give the title compound as a brown oil(yield 4.02 g, 95%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.79 (3H, brs), 4.01 (3H, s), 4.17 (2H,brs), 6.25 (1H, brs), 6.82 (1H, d, J=9.0 Hz), 7.32 (1H, brs), 7.94-7.98(1H, m), 8.77-8.78 (1H, m).

Reference Example 164 tert-butyl{[5-(4-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the titlecompound was obtained as a pale-yellow oil (yield 382 mg, 84%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.79 (3H, s), 4.21 (2H, brs), 6.23 (1H,brs), 7.28-7.34 (2H, m), 7.39-7.43 (2H, m), 7.59-7.66 (3H, m), 8.55 (1H,d, J=2.1 Hz), 8.74-8.76 (1H, m).

Reference Example 165 tert-butyl{[5-(5-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (5-cyano-2-fluorophenyl)boronic acid (198 mg), sodiumcarbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg),the title compound was obtained as a pale-yellow oil (yield 28.9 mg,6%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, brs), 6.28 (1H,brs), 7.21 (1H, t, J=8.7 Hz), 7.35-7.42 (2H, m), 7.49-7.52 (1H, m),7.69-7.73 (2H, m), 8.66 (1H, d, J=2.4 Hz), 8.81-8.83 (1H, m).

Reference Example 166 tert-butyl{[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodiumhydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium(174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL)and water (2 mL), and the mixture was stirred under a nitrogenatmosphere at 90° C. for 1 hr. The reaction mixture was allowed to cool,a saturated aqueous sodium hydrogencarbonate solution was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=1:1) to give thetitle compound as a colorless oil (yield 475 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, s), 3.78 (3H, s), 4.24 (2H,s), 6.22 (1H, d, J=1.1 Hz), 6.69-6.71 (1H, m), 6.90-6.98 (2H, m),7.72-7.36 (2H, m), 7.69-7.73 (1H, m), 8.65 (1H, d, J=2.3 Hz), 8.77 (1H,dd, J=4.9, 1.5 Hz).

Reference Example 167 tert-butyl{[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (2-fluoro-3-formylphenyl)boronic acid (252 mg), sodiumcarbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg),the title compound was obtained as a pale-yellow oil (yield 250 mg,53%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, s), 4.25 (2H, brs), 6.28 (1H,brs), 7.26-7.46 (4H, m), 7.68-7.72 (1H, m), 7.92-7.97 (1H, m), 8.61 (1H,d, J=2.1 Hz), 8.77-8.79 (1H, m), 10.30 (1H, s).

Reference Example 168 tert-butyl{[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (3-acetyl-2-fluorophenyl)boronic acid (273 mg), sodiumcarbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg),the title compound was obtained as a pale-yellow oil (yield 443 mg,91%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.59 (3H, d, J=5.4 Hz), 2.83 (3H, s),4.25 (2H, brs), 6.24 (1H, brs), 7.19-7.36 (4H, m), 7.66-7.70 (1H, m),7.90-7.96 (1H, m), 8.60 (1H, d, J=2.4 Hz), 8.76-8.78 (1H, m).

Reference Example 169 tert-butyl{[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate(254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for1 hr. The reaction mixture was cooled to room temperature. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→1:1) to give the title compound as apale-yellow oil (yield 310 mg, 69%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, s), 4.23 (2H, brs), 6.29 (1H,brs), 7.23-7.27 (1H, m), 7.34-7.39 (2H, m), 7.66-7.73 (2H, m), 8.25-8.27(1H, m), 8.66 (1H, d, J=2.4 Hz), 8.78-8.80 (1H, m).

Reference Example 170 tert-butyl{[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(215 mg), (3-fluoropyridin-4-yl)boronic acid hydrate (120 mg), sodiumhydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) andwater (2 mL), and the mixture was stirred under a nitrogen atmosphere at80° C. for 3 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1) to give the titlecompound as a pale-yellow oil (yield 60 mg, 27%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.61 (3H, s), 4.24 (2H, s), 6.35 (1H,s), 7.22-7.26 (1H, m), 7.35-7.40 (2H, m), 7.71-7.75 (1H, m), 8.47 (1H,d, J=4.8 Hz), 8.50 (1H, d, J=1.3 Hz), 8.70 (1H, d, J=2.1 Hz), 8.81 (1H,dd, J=4.8, 1.6 Hz).

Reference Example 171 tert-butyl{[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (2-chloropyridin-3-yl)boronic acid (237 mg), sodiumhydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) andwater (2 mL), and the mixture was stirred under a nitrogen atmosphere at100° C. for 3 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the titlecompound as a colorless oil (yield 280 mg, 60%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.84 (3H, s), 4.27 (2H, s), 6.30 (1H,s), 7.30-7.39 (3H, m), 7.65-7.73 (2H, m), 8.43-8.45 (1H, m), 8.67 (1H,d, J=2.3 Hz), 8.80 (1H, dd, J=4.9, 1.5 Hz).

Reference Example 172 tert-butyl{[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamateReference Example 173 tert-butyl{[5-(6′-chloro-2,3′-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (6-chloropyridin-3-yl)boronic acid (237 mg), sodiumhydrogencarbonate (252 mg) and tetrakis(triphenylphosphine)palladium (87mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) andwater (2 mL), and the mixture was stirred under a nitrogen atmosphere at90° C. for 3 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1→3:7), and fractionsshowing Rf value of 0.6 (eluent: hexane-ethyl acetate=1:1) werecollected to give the title compound of Reference Example 172 as acolorless oil (yield 100 mg, 22%). Then, fractions showing Rf value of0.4 (eluent: hexane-ethyl acetate=1:1) were collected to give the titlecompound of Reference Example 173 as a pale-yellow powder (yield 100 mg,19%).

Reference Example 172 ¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, s), 4.23(2H, s), 6.24 (1H, s), 7.23-7.38 (3H, m), 7.59-7.63 (1H, m), 7.72 (1H,dd, J=8.3, 2.3 Hz), 8.14 (1H, d, J=2.3 Hz), 8.64 (1H, d, J=2.3 Hz), 8.78(1H, dd, J=4.7, 1.7 Hz).

Reference Example 173 ¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 4.24(2H, s), 6.29 (1H, s), 7.31-7.37 (2H, m), 7.47 (1H, d, J=8.3 Hz),7.64-7.68 (1H, m), 7.76-7.86 (2H, m), 8.38 (1H, dd, J=8.5, 2.5 Hz), 8.51(1H, d, J=1.9 Hz), 8.63 (1H, d, J=2.3 Hz), 8.77 (1H, dd, J=4.9, 1.5 Hz),9.04 (1H, d, J=2.3 Hz).

Reference Example 174 tert-butyl({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate(260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the titlecompound was obtained as a pale-yellow oil (yield 293 mg, 45%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, brs), 3.97 (3H, s), 4.23 (2H,brs), 6.28 (1H, s), 6.69-6.72 (1H, m), 7.26-7.36 (2H, m), 7.49-7.53 (1H,m), 7.75-7.80 (1H, m), 8.22-8.23 (1H, m), 8.26-8.27 (1H, m).

Reference Example 175 tert-butyl({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution of tert-butyl{[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(388 mg) in tetrahydrofuran (8 mL) were added under ice-cooling, sodiumborohydride (41.3 mg) and methanol (3 mL). After stirring at the sametemperature for 30 min, water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give thetitle compound as a colorless oil (yield 238 mg, 61%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.83 (3H, s), 4.24 (2H, brs), 4.65 (2H,brs), 6.19 (1H, brs), 7.15-7.19 (2H, m), 7.34-7.38 (2H, m), 7.51-7.55(1H, m), 7.73-7.76 (1H, m), 8.40-8.41 (1H, m), 8.75-8.77 (1H, m), 1H notdetected.

Reference Example 176 tert-butyl({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

By a similar operation as in Reference Example 175 and using tert-butyl{[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(443 mg), the title compound was obtained as a pale-yellow amorphousform (yield 318 mg, 71%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.50 (3H, d, J=6.3 Hz), 2.83 (3H, s),4.25 (2H, brs), 5.06 (1H, q, J=6.3 Hz), 6.20 (1H, brs), 7.09-7.22 (2H,m), 7.34-7.38 (2H, m), 7.59-7.64 (1H, m), 7.72-7.76 (1H, m), 8.40 (1H,d, J=2.4 Hz), 8.75-8.78 (1H, m), 1H not detected.

Reference Example 177 tert-butyl{[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodiumhydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2mL), and the mixture was stirred under a nitrogen atmosphere 100° C. for2 hr. The reaction mixture was allowed to cool, a saturated aqueoussodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1) to give the titlecompound as a colorless oil (yield 475 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, s), 3.90 (3H, s), 4.24 (2H,s), 6.21 (1H, d, J=1.5 Hz), 6.72-6.79 (1H, m), 7.00-7.09 (2H, m),7.32-7.36 (2H, m), 7.69-7.73 (1H, m), 8.63 (1H, d, J=2.3 Hz), 8.76 (1H,dd, J=4.9, 1.5 Hz).

Reference Example 178 tert-butyl{[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (2-fluoro-6-methoxyphenyl)boronic acid (256 mg), sodiumhydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium(176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water(2 mL), and the mixture was stirred under a nitrogen atmosphere at 100°C. for 20 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1) to give the titlecompound as a colorless oil (yield 100 mg, 21%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.85 (3H, s), 3.58 (3H, s), 4.26 (2H,s), 6.17 (1H, d, J=1.9 Hz), 6.64-6.70 (2H, m), 7.31-7.39 (3H, m),7.71-7.75 (1H, m), 8.60 (1H, d, J=1.9 Hz), 8.76 (1H, dd, J=4.9, 1.5 Hz).

Reference Example 1792-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution (10 mL) of 1-bromo-4-(difluoromethoxy)benzene (500 mg),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (654 mg),potassium acetate (660 mg) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (73.2 mg) in dimethylformamide was stirred at 80° C.for 3 hr. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate and filtered through celite. The filtrate was washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→8:1) togive the title compound as a pale-yellow oil (yield 348 mg, 58%).

¹H-NMR (CDCl₃) δ: 1.35 (12H, s), 6.54 (1H, t, J=73.5 Hz), 7.09 (2H, d,J=7.8 Hz), 7.81 (2H, d, J=7.8 Hz).

Reference Example 180 tert-butyl({5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg),2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(348 mg), sodium carbonate (254 mg) andtetrakis(triphenylphosphine)palladium (174 mg) were suspended indimethoxyethane (10 mL) and water (4 mL), and the mixture was stirredunder a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixturewas allowed to cool to room temperature, water was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the titlecompound as a pale-yellow oil (yield 550 mg, quantitative yield).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.80 (3H, s), 4.21 (2H, brs), 6.13 (1H,brs), 6.57 (1H, t, J=73.2 Hz), 7.06-7.09 (2H, m), 7.21-7.31 (4H, m),7.55-7.59 (1H, m), 8.54 (1H, d, J=2.4 Hz), 8.71-8.73 (1H, m).

Reference Example 181 tert-butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(431 mg), (4-methylpyridin-3-yl)boronic acid (206 mg), sodiumhydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) andwater (2 mL), and the mixture was stirred under a nitrogen atmosphere at80° C. for 6 hr. The reaction mixture was allowed to cool, a saturatedaqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1→0:1) to give the titlecompound as a colorless oil (yield 230 mg, 52%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.11 (3H, s), 2.85 (3H, s), 4.27 (2H,s), 6.15 (1H, s), 7.18 (1H, d, J=4.9 Hz), 7.34-7.39 (2H, m), 7.58-7.62(1H, m), 7.94 (1H, s), 8.49 (1H, d, J=5.3 Hz), 8.64 (1H, d, J=2.3 Hz),8.80 (1H, dd, J=4.9, 1.5 Hz).

Reference Example 182 3-bromo-2-methylpyridine

2-Methylpyridine (46.6 g) was added dropwise to aluminum chloride (200g) and the mixture was stirred at 100° C. To a mixture was addeddropwise bromine (40.0 g) at the same temperature over 1 hr, and themixture was further stirred for 30 min. After cooling, the reactionmixture was poured into ice water, concentrated hydrochloric acid wasadded until the mixture was acidified. The obtained solution was washedwith ethyl acetate, and the aqueous layer was basified with a 8 mol/Laqueous sodium hydroxide solution. After extraction with diethyl ether,the extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-diethylether=10:1) to give the title compound as a colorless oil (yield 5.09 g,12%).

¹H-NMR (CDCl₃) δ: 2.67 (3H, s), 6.98-7.03 (1H, m), 7.78-7.82 (1H, m),8.40-8.44 (1H, m).

Reference Example 183 tert-butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

To a solution of 3-bromo-2-methylpyridine (504 mg) in diethyl ether (15mL) was added a 1.62 mol/L solution (2 mL) of n-butyl lithium in hexaneat −78° C., and the mixture was stirred at the same temperature for 15min. Thereto was added triisopropoxyborane (1.22 mL) at the sametemperature, and the obtained mixture was stirred at 0° C. for 1 hr.Methanol (2 mL) was added to the reaction mixture, and the mixture wasconcentrated under reduced pressure. tert-Butyl({5-bromo-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(432 mg), sodium carbonate (1.15 g),tetrakis(triphenylphosphine)palladium (174 mg), 1,2-dimethoxyethane (20mL) and water (10 mL) was added to the residue, and the mixture wasstirred under a nitrogen atmosphere at 105° C. for 1 hr. The reactionmixture was allowed to cool to room temperature, water was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith a saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1) togive the title compound as a brown oil (yield 282 mg, 22%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.09 (3H, s), 2.85 (3H, s), 4.27 (2H,brs), 6.14 (1H, brs), 7.10-7.14 (1H, m), 7.26-7.38 (3H, m), 7.56-7.60(1H, m), 8.54-8.56 (1H, m), 8.60-8.61 (1H, m), 8.78-8.80 (1H, m).

Reference Example 184 6-methylnicotinamide

A mixture of methyl 6-methylnicotinate (13.9 g) and 28% aqueous ammonia(140 mL) was stirred at room temperature for 4 hr. The reaction mixturewas concentrated under reduced pressure, and the residue wasrecrystallized from ethanol to give the title compound as a white solid(yield 8.98 g, 72%).

¹H-NMR (CDCl₃) δ: 2.63 (3H, s), 5.60-6.20 (2H, brm), 7.25-7.28 (1H, m),8.04-8.07 (1H, m), 8.90 (1H, d, J=2.1 Hz).

Reference Example 185 6-methylpyridine-3-amine

Bromine (1.0 mL) was added to a 4 mol/L aqueous sodium hydroxidesolution (60 mL) at 0° C., and the mixture was stirred at the sametemperature for 15 min. 6-Methylnicotinamide (2.4 g) was added to theobtained solution over 10 min, and the mixture was stirred at roomtemperature for 30 min and further stirred at 75° C. for 4 hr. Thereaction mixture was allowed to cool to room temperature, and extractedwith ethyl acetate:THF=2:1. The extract was washed with a small amountof saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. Recrystallization of the residuefrom ethyl acetate-hexane gave the title compound as a pale-yellow solid(yield 0.93 g, 49%).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.54 (2H, brs), 6.89-6.95 (2H, m),7.99-8.01 (1H, m).

Reference Example 186 6-methylpyridin-3-ylsulfonyl chloride

To a mixture of 6-methylpyridine-3-amine (449 mg) and concentratedhydrochloric acid (5 mL) was added a solution of sodium nitrite (857 mg)in water (2 mL) at 0° C., and the mixture was stirred at the sametemperature for 10 min. To the mixture was added a solution ofconcentrated hydrochloric acid (2.5 mL), copper sulfate (69 mg) andsodium hydrogen sulfite (5.08 g) in water (8 mL) at 0° C., and themixture was stirred at room temperature for 30 min. The reaction mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=10:1) to give the titlecompound as a pale-yellow solid (yield 0.12 g, 15%).

¹H-NMR (CDCl₃) δ: 2.73 (3H, s), 7.40-7.43 (1H, m), 8.16-8.20 (1H, m),9.11-9.12 (1H, m).

Reference Example 187 tert-butyl({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution of tert-butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) intetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 31 mg) at0° C., and the mixture was stirred at the same temperature for 10 min. Asolution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3-ylsulfonylchloride (117 mg) in tetrahydrofuran was added at the same temperature.After stirring at room temperature for 30 min, water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1) to give the title compound as a brown oil (yield 213 mg,79%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.66 (3H, s), 2.79 (3H, s), 4.17 (2H,brs), 6.26 (1H, brs), 7.26-7.33 (2H, m), 8.03-8.07 (1H, m), 9.01-9.02(1H, m).

Reference Example 188 tert-butyl({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

A suspension of tert-butyl({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate(119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under anitrogen atmosphere at 105° C. for 1 hr. The reaction mixture wasallowed to cool to room temperature, water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=1:1) to give thetitle compound as a pale-yellow oil (yield 87 mg, 41%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.62 (3H, m), 2.82 (3H, s), 4.23 (2H,brs), 6.29 (1H, s), 7.18-7.27 (2H, m), 7.33 (1H, s), 7.54-7.57 (1H, m),7.72-7.75 (1H, m), 8.26-8.27 (1H, m), 8.53 (1H, s).

Reference Example 1895-(2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g),(2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate(2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were addedto a degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL),and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5hr. The reaction mixture was allowed to cool, a saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:3) to give the title compound as a colorlessoil (yield 2.25 g, 68%).

¹H-NMR (CDCl₃) δ: 6.71 (1H, d, J=1.7 Hz), 7.24-7.28 (1H, m), 7.42-7.48(4H, m), 7.62-7.68 (1H, m), 7.70-7.76 (1H, m), 8.14 (1H, d, J=1.9 Hz),8.28-8.31 (1H, m), 9.90 (1H, s).

Reference Example 190 5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde

5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(2.25 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL),a 8 mol/L aqueous sodium hydroxide solution (20 mL) was added dropwiseat room temperature and the mixture was stirred for 1 hr. The reactionmixture was diluted with saturated brine, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. Ethyl acetate was added to the residue and insoluble crystalswere collected by filtration to give the title compound as pale-browncrystals (yield 1.03 g, 79%).

¹H-NMR (DMSO-d₆) δ: 6.99 (1H, d, J=1.5 Hz), 7.43-7.48 (1H, m), 7.88 (1H,s), 8.12-8.15 (1H, m), 8.27-8.34 (1H, m), 9.77 (1H, s), 12.28 (1H, brs).

Reference Example 1914-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde

5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) wasdissolved in N,N-dimethylformamide (20 mL), N-chlorosuccinimide (641 mg)was added and the mixture was stirred at 80° C. for 40 min. Aftercooling, water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=3:2→1:1) to give the titlecompound as a colorless powder (yield 320 mg, 44%).

¹H-NMR (DMSO-d₆) δ: 7.49-7.54 (1H, m), 7.86 (1H, d, J=2.3 Hz), 8.12-8.19(1H, m), 8.30-8.32 (1H, m), 9.80 (1H, s), 12.48 (1H, brs).

Reference Example 1924-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (20 mL) of4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (270 mg) intetrahydrofuran was added sodium hydride (60% in oil, 100 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (530 mg)was added dropwise and the mixture was stirred for 30 min.3-Pyridylsulfonyl chloride (321 mg) was added, and the mixture wasfurther stirred for 1 hr. The reaction mixture was diluted withsaturated brine, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=1:1→1:4), and crystallized from diethyl ether to give the titlecompound as colorless crystals (yield 358 mg, 81%).

¹H-NMR (CDCl₃) δ: 7.35-7.39 (1H, m), 7.42-7.46 (1H, m), 7.69-7.73 (1H,m), 7.76-7.82 (1H, m), 8.14 (1H, s), 8.39-8.41 (1H, m), 8.64 (1H, dd,J=2.5 Hz, 0.6 Hz), 8.89 (1H, dd, J=4.8 Hz, 1.6 Hz), 9.97 (1H, s).

Reference Example 193 tributyl(2-thienyl)stannane

A solution (10 mL) of 2-bromothiophene (1.0 g) in tetrahydrofuran wascooled to −70° C., and a 1.6 mol/L solution (4.2 mL) of n-butyllithiumin hexane was added dropwise. After stirring at the same temperature for30 min, tributyltin chloride (2.1 g) was added dropwise. After furtherstirring for 1 hr, water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residual oil (2.4 g) containing the titlecompound was used for the next step without purification.

Reference Example 194 tert-butyl methyl{[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

To a solution of crude tributyl(2-thienyl)stannane (1.1 g) andtert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116mg), and the mixture was stirred under a nitrogen atmosphere at 120° C.for 1 hr. The reaction mixture was allowed to cool to room temperatureand the solvent was evaporated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=4:1) to give the title compound as a pale-yellow oil (yield 315mg, 73%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, s), 4.22 (2H, brs), 6.25 (1H,brs), 7.04-7.07 (1H, m), 7.16-7.17 (1H, m), 7.27-7.31 (2H, m), 7.36-7.37(1H, m), 7.62-7.66 (1H, m), 8.58-8.59 (1H, m), 8.71-8.73 (1H, m).

Reference Example 195 3-methyl-2-(tributylstannyl)pyridine

A solution (10 mL) of 2-bromo-3-methylpyridine (1.0 g) intetrahydrofuran was cooled to −70° C., and a 1.6 mol/L solution (4.0 mL)of n-butyllithium in hexane was added dropwise. After stirring at thesame temperature for 15 min, tributyltin chloride (2.2 g) was addeddropwise. After further stirring for 1 hr, water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1) to give the title compound as a colorless oil (yield 1.75g, 79%).

¹H-NMR (CDCl₃) δ: 0.85-0.95 (9H, m), 1.11-1.17 (6H, m), 1.29-1.37 (6H,m), 1.49-1.57 (6H, m), 2.36 (3H, s), 6.99-7.03 (1H, m), 7.31-7.34 (1H,m), 8.52-8.54 (1H, m).

Reference Example 196 tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g), tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluenewas stirred under a nitrogen atmosphere at 120° C. for 30 hr. Themixture was cooled to room temperature and the solvent was evaporatedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: hexane-ethyl acetate=4:1) to give thetitle compound as a colorless oil (yield 129 mg, 22%).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.80 (3H, brs), 4.25 (2H, brs), 6.26(1H, brs), 7.23-7.27 (2H, m), 7.39-7.44 (1H, m), 7.60 (1H, d, J=6.9 Hz),7.99-8.03 (1H, m), 8.36 (1H, d, J=4.5 Hz), 8.78-8.80 (1H, m), 8.86-8.87(1H, m).

Reference Example 197 tert-butyl{[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (3 mL) of tert-butyl{[5-(2-fluoro-3-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(182 mg) in 2-propanol were added hydroxylamine hydrochloride (40 mg)and sodium acetate (47 mg). After stirring at room temperature for 3 hr,saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=8:1→3:1) to give the title compound as a pale-yellow oil (yield150 mg, 80%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, s), 6.22 (1H,s), 7.15-7.19 (2H, m), 7.31-7.35 (2H, m), 7.67-7.71 (1H, m), 7.76-7.85(1H, m), 8.27 (1H, s), 8.63 (1H, d, J=2.1 Hz), 8.76-8.78 (1H, m), 1H notdetected.

Reference Example 198 tert-butyl{[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (5 mL) of tert-butyl{[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(150 mg) in tetrahydrofuran were added triethylamine (93 mg) andmethanesulfonyl chloride (84 mg) at room temperature. The reactionmixture was stirred at 70° C. for 8 hr, and cooled to room temperature.Water was added and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=8:1→3:1) to give the title compound as a pale-yellow oil (yield106 mg, 73%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, s), 4.24 (2H, s), 6.28 (1H,brs), 7.25-7.40 (3H, m), 7.48-7.53 (1H, m), 7.66-7.70 (2H, m), 8.62 (1H,d, J=2.7 Hz), 8.80-8.82 (1H, m).

Reference Example 199 tert-butyl{[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(430 mg), (4-bromo-3-thienyl)boronic acid (248 mg), sodium carbonate(254 mg) and tetrakis(triphenylphosphine)palladium (116 mg), the titlecompound was obtained as a pale-yellow oil (yield 470 mg, 92%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.84 (3H, brs), 4.26 (2H, brs),6.21-6.22 (1H, m), 7.18-7.19 (1H, m), 7.30-7.39 (3H, m), 7.63-7.67 (1H,m), 8.57-8.58 (1H, m), 8.74-8.76 (1H, m).

Reference Example 200 tert-butyl{[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (5 mL) of tert-butyl{[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(470 mg) in N,N-dimethylformamide were added zinc cyanide (215 mg) andtetrakis(triphenylphosphine)palladium (212 mg) and the mixture wassufficiently degassed. The mixture was stirred with heating at 120° C.for 18 hr and cooled to room temperature. Water and ethyl acetate wereadded and the mixture was filtered through celite. The filtrate wasconcentrated under reduced pressure and the residue was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as apale-yellow oil (yield 297 mg, 71%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, brs), 4.25 (2H, brs),6.34-6.35 (1H, m), 7.35-7.39 (2H, m), 7.48 (1H, br), 7.65-7.68 (1H, m),7.87 (1H, d, J=3.0 Hz), 8.53-8.54 (1H, m), 8.78-8.79 (1H, m).

Example 1N-methyl-1-[5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

5-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (230 mg) wasdissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1 mL)of methylamine in tetrahydrofuran was added, and the mixture was stirredat room temperature for 2 hr. The reaction mixture was added to asolution of sodium borohydride (76 mg) in methanol (5 mL), and themixture was stirred at the same temperature for 20 min. The reactionmixture was diluted with ethyl acetate, washed successively with asaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: ethyl acetate-methanol=1:0→1:1) andfurther by HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1%trifluoroacetic acid-containing acetonitrile=97:3-0.1% trifluoroaceticacid-containing acetonitrile) to give trifluoroacetate of the titlecompound. The obtained trifluoroacetate was neutralized with a saturatedaqueous sodium hydrogencarbonate solution, extracted with ethyl acetate,washed successively with a saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethylacetate solution (1 mL) and ethanol (5 mL) were added, and the mixturewas concentrated under reduced pressure and crystallized from ethylacetate-ethanol to give the title compound (yield 85 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.97-4.00 (2H, s), 6.50 (1H, s),7.14-7.16 (2H, m), 7.35-7.45 (3H, m), 7.62-7.70 (1H, m), 7.78-7.83 (2H,m), 8.47-8.48 (1H, m), 8.84-8.86 (1H, m), 9.08 (2H, br), 1H notdetected.

Example 21-{1-[(6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

1-[(6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(59 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/Lsolution (0.25 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas added to a solution of sodium borohydride (19 mg) in methanol (2mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith water and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: ethylacetate-methanol=1:0→1:1) to give a free salt (48 mg) of the titlecompound. The obtained free salt was dissolved in ethyl acetate (2 mL),a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added, andthe mixture was left standing at room temperature for 30 min. Theprecipitated crystals were collected by filtration, washed with ethylacetate to give the title compound (yield 39 mg, 58%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 6.45 (1H,s), 6.91-6.94 (1H, m), 7.16-7.18 (2H, m), 7.36-7.45 (3H, m), 7.59-7.63(1H, m), 7.72 (1H, s), 8.09-8.10 (1H, m), 8.91 (2H, br).

Example 3N-methyl-1-{1-[6-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

By a similar reaction as in Example 2 and using1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (100mg), the title compound was obtained (yield 58 mg, 47%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.78 (3H, s), 3.95-3.99 (2H, m),6.39-6.42 (2H, m), 7.20-7.23 (3H, m), 7.35-7.43 (3H, m), 7.63 (1H, s),7.82-7.85 (2H, m), 9.00 (2H, br), 1H not detected.

Example 4N-methyl-1-{1-[2-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

1-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (173mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.25mL) of methylamine in tetrahydrofuran was added, and the mixture wasstirred at room temperature for 12 hr. The reaction mixture was added toa solution (2 mL) of sodium borohydride (76 mg) in methanol, and themixture was stirred at room temperature for 20 min. A saturated aqueoussodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate→ethyl acetate-methanol=1:4) togive a free salt of the title compound. To a solution (3 mL) of theobtained free salt in ethanol was added a 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL). The solvent was evaporated underreduced pressure, and the residue was recrystallized from ethanol togive the title compound (yield 126 mg, 59%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.77 (3H, d, J=4.5 Hz), 3.95-3.99 (2H,m), 4.80 (1H, br), 6.28-6.30 (1H, m), 6.41-6.47 (2H, m), 7.10-7.19 (3H,m), 7.32-7.44 (3H, m), 7.88 (1H, s), 8.25-8.27 (1H, m), 9.19 (2H, br).

Example 5N-methyl-1-{1-[2-(methylamino)pyrimidin-5-ylsulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

By a similar reaction as in Example 2 and using1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(100 mg), the title compound was obtained (yield 64 mg, 57%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.80-2.82 (3H, s), 3.98 (2H, s), 6.47(1H, s), 7.23-7.26 (2H, m), 7.39-7.43 (3H, m), 7.66-7.67 (1H, m),7.96-7.97 (1H, m), 8.11-8.12 (1H, m), 8.48-8.52 (1H, m), 8.97 (2H, br).

Example 6N-methyl-1-[2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

By a similar reaction as in Example 2 and using2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(235 mg), an ethanol (1 equivalent) adduct of the title compound wasobtained as a solid (yield 110 mg, 39%).

¹H-NMR (DMSO-d₆) δ: 1.06 (3H, t, J=7.2 Hz), 2.43-2.50 (6H, m), 3.44 (2H,dd, J=14.1, 7.2 Hz), 3.91-3.94 (2H, m), 6.47 (1H, s), 7.21-7.43 (2H, m),7.36-7.41 (3H, m), 7.56-7.63 (1H, m), 7.82-7.88 (1H, m), 8.53 (1H, s),8.87-8.93 (3H, m), 2H not detected.

Example 7N-methyl-1-[1-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-methanaminedihydrochloride

1-[(2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(148 mg) was dissolved in absolute tetrahydrofuran (10 mL), a 2 mol/Lsolution (1.25 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred overnight at room temperature. The reaction mixturewas added to a solution of sodium borohydride (95 mg) in methanol (3.0mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed with saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL), di-tert-butyl bicarbonate (0.55 g), sodiumhydrogencarbonate (0.25 g) and water (10 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed successively with a saturated aqueoussodium hydrogencarbonate solution and saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),manganese dioxide (75% chemically treated product, 1.5 g) was added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give an oil. The obtained oil wasdissolved in ethanol (1 mL), a 4 mol/L hydrogen chloride-ethyl acetatesolution (1 mL) was added and the mixture was stirred at roomtemperature for 3 hr. The solvent was evaporated under reduced pressureto give a solid (67 mg). Recrystallization from ethanol gave the titlecompound as a colorless solid (yield 34 mg, 18%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 2.70 (3H, s), 3.98 (2H, s), 6.50 (1H,s), 7.18-7.20 (2H, m), 7.38-7.47 (3H, m), 7.76-7.77 (1H, m), 8.59 (2H,s), 8.88 (2H, br), 1H not detected.

Example 81-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(1.52 g) was dissolved in methanol (30 mL), a 40% methylamine methanolsolution (3.57 g) was added at room temperature and the mixture wasstirred for 30 min. Sodium borohydride (523 mg) was added at roomtemperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloricacid (50 mL) was added and the mixture was stirred for 5 min. Thereaction mixture was basified with a saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→7:3) to give a free salt of the titlecompound as a pale-yellow oil (yield 1.30 g). The obtained free salt(750 mg) was dissolved in ethyl acetate (30 mL), a solution of fumaricacid (278 mg) in methanol (3 mL) was added dropwise at room temperature.After stirring for 30 min, the obtained crystals were collected byfiltration, and washed with ethyl acetate to give the title compound ascolorless crystals (yield 912 mg, 74%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H,d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 7.49-7.56 (1H, m),7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m), 8.56-8.57(1H, m), 8.87-8.89 (1H, m), 3H not detected.

melting point 201-203° C.

Example 9N-methyl-1-{1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanaminedihydrochloride

1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(340 mg) was dissolved in ethanol (34 mL), a 40% methylamine methanolsolution (695 mg) was added at room temperature and the mixture wasstirred for 30 min. Sodium borohydride (102 mg) was added at roomtemperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloricacid (10 mL) was added and the mixture was stirred for 5 min. Thereaction mixture was basified with a saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→7:3) and dissolved in ethyl acetate (5 mL). A4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added andthe mixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as pale-redcrystals (yield 288 mg, 69%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, t, J=5.5 Hz), 4.00 (2H, t, J=5.5 Hz), 6.60(1H, d, J=1.8 Hz), 7.18-7.21 (1H, m), 7.63-7.81 (4H, m), 7.91-8.00 (2H,m), 8.58 (1H, d, J=1.8 Hz), 8.90-8.92 (1H, m), 9.48-9.57 (2H, m), 1H notdetected.

Example 10N-methyl-1-[4-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

By a similar reaction as in Example 2 and using4-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(171 mg), the title compound was obtained (yield 110 mg, 50%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.57 (3H, s), 3.96-4.00 (2H, m),6.98-7.01 (2H, m), 7.36-7.43 (3H, m), 7.55-7.60 (1H, m), 7.79-7.82 (2H,m), 8.43-8.44 (1H, m), 8.84-8.86 (1H, m), 9.13% (2H, br), 1H notdetected.

Example 11N-methyl-1-[4-methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

4-Methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(262 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution(1.0 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 4 hr. The reaction mixture was addedto a solution (5 mL) of sodium borohydride (76 mg) in methanol, and themixture was stirred at room temperature for 20 min. Water was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethylacetate-methanol=1:0→1:1) and further by HPLC (ODS, 0.1% trifluoroaceticacid-containing water-0.1% trifluoroacetic acid-containingacetonitrile=9:1→0.1% trifluoroacetic acid-containing acetonitrile) togive trifluoroacetate of the title compound. The obtainedtrifluoroacetate was neutralized with a saturated aqueous sodiumhydrogencarbonate solution, extracted with ethyl acetate, washedsuccessively with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (3 mL), a 4 mol/L solution (2 mL) of hydrogenchloride in ethyl acetate was added. After allowing to stand at roomtemperature for 30 min, the precipitate was collected by filtration andwashed with ethyl acetate to give the title compound (yield 141 mg,47%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.59 (3H, s), 4.01 (2H, s), 6.88-6.90(2H, m), 7.27-7.45 (4H, m), 7.71-7.74 (2H, m), 7.95-7.99 (1H, m),8.68-8.70 (1H, m), 8.88 (2H, br).

Example 121-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminedihydrochloride

1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(294 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution(1.0 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 1 hr. The mixture was heated to 40°C., and the mixture was further stirred for 4 hr. The reaction mixturewas added to a solution (5 mL) of sodium borohydride (76 mg) inmethanol, and the mixture was stirred at room temperature for 1 hr.Water was added, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→0:1) to give a free salt of the title compound.To a solution (3 mL) of the obtained free salt in ethyl acetate wasadded a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). Afterallowing to stand at room temperature for 30 min, the precipitate wascollected by filtration, and washed with ethyl acetate to give the titlecompound (yield 196 mg, 53%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.25 (3H, s), 2.60 (3H, m), 3.45 (3H,s), 3.95-3.99 (2H, m), 4.86 (1H, br), 6.99-7.01 (2H, m), 7.13 (1H, s),7.32-7.39 (3H, m), 7.59 (1H, s), 8.96 (2H, br).

Example 131-{1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

By a similar reaction as in Example 12 and using1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(378 mg), the title compound was obtained as a solid (yield 238 mg,55%).

¹H-NMR (DMSO-d₆) δ: 1.67 (3H, s), 1.79 (3H, s), 2.58 (3H, s), 3.67 (3H,s), 3.99 (2H, s), 6.97-6.99 (2H, m), 7.33-7.41 (3H, m), 7.73 (1H, s),8.90 (2H, br).

Example 141-{1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(295 mg), a free salt (297 mg) of the compound of Example 13 wasobtained as an oil. The obtained oil was dissolved in toluene (10 mL)and methanol (10 mL), 10% palladium carbon (50% containing water, 30 mg)and 20% sodium ethoxide-ethanol solution (309 mg) were added, and themixture was stirred at under a hydrogen atmosphere at room temperaturefor 24 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate solution (5 mL) and a 4 mol/L hydrogen chloride-ethyl acetatesolution (1 mL) was added. After allowing to stand at room temperaturefor 30 min, the precipitate was collected by filtration, and washed withethyl acetate to give the title compound (yield 221 mg, 72%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 1.90 (3H, s), 2.59 (3H, m), 3.63 (3H,s), 3.99 (2H, s), 6.99-7.02 (2H, m), 7.35-7.40 (3H, m), 7.51 (1H, s),7.66 (1H, s), 8.87 (2H, br).

Example 151-{1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminetrifluoroacetate

To a solution (1 mL) of1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(27.7 mg) in tetrahydrofuran was added a 2 mol/L solution (0.1 mL) ofmethylamine in tetrahydrofuran, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to a solution (1mL) of sodium borohydride (7.6 mg) in methanol, and the mixture wasstirred at room temperature for 20 min. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroaceticacid-containing acetonitrile (97:3)→0.1% trifluoroacetic acid-containingacetonitrile alone), and triturated with diisopropyl ether to give thetitle compound as a solid (yield 12.1 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.06 (3H, s), 2.58 (3H, s), 2.62 (3H,s), 4.03 (2H, s), 7.05-7.07 (2H, m), 7.37-7.44 (3H, m), 7.67 (1H, s),8.62 (2H, br).

Example 16[5-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

To a solution of5-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(382 mg) in methanol (5 mL) and tetrahydrofuran (2 mL) was added a 40%methylamine methanol solution (1.1 mL), and the mixture was stirred atroom temperature for 4 hr. Sodium borohydride (51 mg) was added to thereaction mixture, and the mixture was further stirred for 15 min. Thereaction mixture was concentrated under reduced pressure. A saturatedaqueous sodium hydrogencarbonate solution (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: ethyl acetate) togive a free salt of the title compound (yield 342 mg). To a solution ofthe obtained free salt (336 mg) in ethanol (5 mL) was added a 4% mol/Lhydrogen chloride-ethyl acetate solution (5.0 mL), and the mixture wasstirred at room temperature for 30 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol to give the title compound as white crystals (yield 197 mg,46%).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 2.59 (3H, t, J=5.4 Hz), 4.01 (2H, t,J=5.4 Hz), 7.03-7.08 (1H, m), 7.21-7.28 (2H, m), 7.51-7.64 (2H, m),7.82-7.86 (2H, m), 8.53 (1H, d, J=2.4 Hz), 8.80-8.89 (3H, m).

Example 171-[1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

To a solution (3 mL) of tert-butyl{[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(70 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethylacetate solution (1 mL), and the mixture was stirred at room temperaturefor 3 hr. The solvent was evaporated under reduced pressure, and theresidue was crystallized from ethanol-ethyl acetate to give the titlecompound (yield 29 mg, 49%).

¹H-NMR (DMSO-d₆) δ: 2.56 (3H, s), 4.04 (2H, s), 6.48 (1H, s), 6.99-7.02(2H, m), 7.25-7.36 (4H, m), 7.66-7.69 (1H, m), 7.83 (1H, s), 8.60-8.62(1H, m), 8.79 (2H, br).

Example 185-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyrimidine-2-amine

To a solution (4 mL) of1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(139 mg) in tetrahydrofuran was added a 0.5 mol/L ammonia-dioxanesolution (4 mL). After stirring at room temperature for 1 hr, asaturated aqueous sodium hydrogencarbonate solution was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved in atetrahydrofuran (5 mL), a 2 mol/L solution (0.75 mL) of methylamine intetrahydrofuran was added, and the mixture was stirred overnight at roomtemperature. The reaction mixture was added to a solution (2 mL) ofsodium borohydride (38 mg) in methanol, and the mixture was stirred atroom temperature for 5 min. A saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by HPLC (ODS, 0.1%trifluoroacetic acid-containing water-0.1% trifluoroaceticacid-containing acetonitrile=9:1→0.1% trifluoroacetic acid-containingacetonitrile) to give trifluoroacetate of the title compound. Theobtained trifluoroacetate was neutralized with a saturated aqueoussodium hydrogencarbonate solution, extracted with ethyl acetate, washedsuccessively with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and crystallizedcrystals were washed with diisopropyl ether to give the title compoundas a colorless solid (yield 23 mg, 17%).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 3.52 (2H, s), 6.31 (1H, s), 7.26-7.40(6H, m), 7.94 (2H, br), 8.00 (2H, s), 1H not detected.

Example 191-[(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Under a nitrogen atmosphere, a solution of ethyl1-(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate(242 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., a 1.5 mol/Lsolution (2.0 mL) of diisobutylaluminum hydride in toluene was addedwith stirring. After stirring at the same temperature for 1 hr, themixture was warmed to −20° C. over 1 hr. Water (30 mL) was added and,after stirring at the same temperature for 5 min, the mixture wasallowed to warm to 0° C. over 10 min. Ethyl acetate (20 mL) was addedand, after stirring at the same temperature for 15 min, the mixture wasstirred at room temperature for 20 min. The reaction mixture in a gelstate was filtered through celite, and celite was washed with ethylacetate. The organic layer was separated from the filtrate, washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL), manganese dioxide (75% chemically treatedproduct, 2.0 g) was added, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was filtered through celite,and celite was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, the residue was dissolved in absolutetetrahydrofuran (5 mL), a 2 mol/L solution (0.6 mL) of methylamine intetrahydrofuran was added, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to a solution ofsodium borohydride (45 mg) in methanol (2 mL), and the mixture wasstirred at the same temperature for 20 min. The reaction mixture wasdiluted with ethyl acetate, washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL),di-tert-butyl bicarbonate (0.22 g), sodium hydrogencarbonate (84 mg) andwater (5 mL) were added, and the mixture was stirred at room temperaturefor 30 min. The reaction mixture was diluted with ethyl acetate, washedwith saturated brine, dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (20 mL), manganese dioxide (75% chemically treatedproduct, 1.0 g) was added, and the mixture was stirred at roomtemperature for 2 days. The reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=19:1→0:1)to give an oil. The obtained oil was dissolved in ethanol (1 mL), and a4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. Afterstirring at room temperature for 2 hr, the solvent was evaporated underreduced pressure, and the residue was triturated with ethylacetate-ethanol to give the title compound as a brown solid (yield 8.5mg, 3%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 4.02-4.05 (2H, m), 6.49 (1H, s),7.16-7.19 (2H, m), 7.32-7.44 (3H, m), 7.79 (1H, s), 7.92-7.99 (2H, m),8.29-8.30 (1H, m), 8.97 (2H, br), 9.23-9.24 (1H, m), 1H not detected.

Example 20N-methyl-1-[5-phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

Under a nitrogen atmosphere, a solution of ethyl5-phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (567 mg) intetrahydrofuran (16 mL) was cooled to −78° C., a 1.5 mol/L solution (6.4mL) of diisobutylaluminum hydride in toluene was added with stirring.The reaction mixture warmed to −20° C. over 1 hr. Water (75 mL) wasadded, and after stirring at the same temperature for 5 min, the mixturewas allowed to warm to 0° C. over 10 min. Ethyl acetate (75 mL) wasadded, and after stirring at the same temperature for 15 min, themixture was stirred at room temperature for 20 min. The reaction mixturewas filtered through celite, and celite was washed with ethyl acetate.The organic layer was separated from the filtrate, washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was dissolved in tetrahydrofuran (30 mL),manganese dioxide (75% chemically treated product, 5.0 g) was added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure and theresidue was dissolved in absolute tetrahydrofuran (15 mL). A 2 mol/Lsolution (1.5 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred overnight at room temperature. The reaction mixturewas added to a solution of sodium borohydride (66 mg) in methanol (5mL), and the mixture was stirred at the same temperature for 20 min. Asaturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by HPLC (ODS, 0.1% trifluoroacetic acid-containingwater-0.1% trifluoroacetic acid-containing acetonitrile=9:1→0.1%trifluoroacetic acid-containing acetonitrile) to give trifluoroacetateof the title compound. The obtained trifluoroacetate was neutralizedwith a saturated aqueous sodium hydrogencarbonate solution, extractedwith ethyl acetate, washed successively with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give a free salt (59 mg) of the title compound. The obtainedfree salt (59 mg) was dissolved in methanol (2 mL) and ethyl acetate (2mL), and fumaric acid (21 mg) was added. The solvent was evaporatedunder reduced pressure, and recrystallization from ethylacetate-methanol gave the title compound as a pale-yellow solid (yield41 mg, 6%).

¹H-NMR (DMSO-d₆) δ: 2.42 (3H, s), 3.82 (2H, s), 6.41 (1H, s), 6.47 (2H,s), 7.09-7.12 (2H, m), 7.29-7.38 (3H, m), 7.63 (1H, s), 7.80-7.83 (1H,m), 7.91-7.96 (1H, m), 9.48-9.50 (1H, m), 3H not detected.

Example 21N-methyl-1-[1-(5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminefumarate

To a solution (5 mL) of tert-butyl{[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(237 mg) in tetrahydrofuran was added hydrazine (160 mg) at roomtemperature with stirring. After stirring at the same temperature for 3hr, a saturated aqueous sodium hydrogencarbonate solution was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), manganese dioxide (75% chemically treatedproduct, 1.0 g) was added, and the mixture was stirred at roomtemperature for 10 min. The reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1)to give an oil. The obtained oil was dissolved in ethanol (2 mL), and a4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. Afterstirring at room temperature for 2 hr, the solvent was evaporated underreduced pressure, a saturated aqueous sodium hydrogencarbonate solutionwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residue(93 mg) was dissolved in ethanol (3 mL), and fumaric acid (29 mg) wasadded. After allowing to stand at room temperature for 30 min, theprecipitated crystals were collected by filtration and washed withmethanol to give the title compound as a colorless solid (yield 91 mg,40%).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 2.38 (3H, s), 3.75 (2H, s), 6.37 (1H,s), 6.47 (2H, s), 7.15-7.17 (2H, m), 7.36-7.45 (4H, m), 7.58 (1H, s),8.28 (1H, s), 8.68 (1H, s), 3H not detected.

Example 225-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridin-2-olhydrochloride

tert-Butyl{[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(175 mg) was dissolved in tetrahydrofuran (10 mL), a 8 mol/L aqueoussodium hydroxide solution (3.8 mL) was added, and the mixture wasstirred at 50° C. for 2 days. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→0:1) togive a free salt of the title compound. To a solution (1 mL) of theobtained free salt in ethanol was added a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL). After stirring at roomtemperature for 4 hr, the solvent was evaporated under reduced pressure,and the residue was crystallized from ethanol-ethyl acetate to give thetitle compound (yield 40 mg, 27%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.97-4.01 (2H, m), 6.32-6.36 (1H, m),6.47 (1H, s), 7.20-7.23 (4H, m), 7.37-7.48 (3H, m), 7.66 (1H, s), 8.94(2H, br), 12.35 (1H, br).

Example 235-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridine-2-carbonitrilehydrochloride

Under an argon atmosphere, a mixture of tert-butyl{[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg), zinc (II) cyanide (51 mg),tetrakis(triphenylphosphine)palladium (50 mg) and N,N-dimethylformamide(4 mL) was stirred at 100° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed successively with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give an oil.The obtained oil was dissolved in ethyl acetate (2 mL), and a 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL) was added. Afterstirring at room temperature for 1 hr, the solvent was evaporated underreduced pressure, and the residue was crystallized from ethanol to givethe title compound (yield 57 mg, 68%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.98 (2H, s), 6.52 (1H, s), 7.15-7.17(2H, m), 7.37-7.47 (3H, m), 7.79 (1H, s), 8.04-8.07 (1H, m), 8.22-8.24(1H, m), 8.61-8.62 (1H, m), 9.03 (2H, br).

Example 24N-methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

tert-Butyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(113 mg) was dissolved in ethanol (2 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was concentrated underreduced pressure, and the residue was recrystallized from ethanol togive the title compound (yield 40 mg, 38%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.53 (6H, m), 3.97-3.99 (2H, m), 6.46 (1H, s),7.16-7.18 (2H, m), 7.38-7.44 (4H, m), 7.65-7.75 (2H, m), 8.34 (1H, s),8.98 (2H, br), 1H not detected.

Example 25N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanaminehydrochloride

By a similar operation as in Example 24 and using tert-butyl{[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(182 mg), the title compound was obtained as colorless crystals (yield64 mg, 41%).

¹H-NMR (CDCl₃) δ: 2.60 (3H, s), 3.98 (2H, brs), 6.57 (1H, brs), 7.00(1H, brd, J=4.5 Hz), 7.16 (1H, brs), 7.26-7.31 (2H, m), 7.70 (2H, brs),8.61 (1H, brs), 8.73 (1H, brs), 9.86 (2H, brs).

Example 261-[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

tert-Butyl{[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(293 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid(1 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 3 hr. The reaction solution was basified by addingdropwise to a 6% aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free salt of the title compound as a pale-yellow oil. Theobtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-ethanol to give the title compound ascolorless crystals (yield 110 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.47-2.51 (3H, m), 3.97 (2H, t, J=6.0 Hz), 6.52-6.53(1H, m), 7.15-7.26 (4H, m), 7.57-7.61 (1H, m), 7.79-7.85 (2H, m), 8.00(1H, d, J=2.4 Hz), 8.85-8.87 (1H, m), 9.22 (2H, br), 1H not detected.

Example 27N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(210 mg), the title compound was obtained as colorless crystals (yield67 mg, 34%). More specifically, tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(210 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid(1 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 2 hr. The reaction solution was basified by addingdropwise to a 6% aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free salt of the title compound as a pale-yellow oil. Theobtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-ethanol to give the title compound ascolorless crystals (yield 67 mg, 34%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.49-2.53 (3H, m), 4.00 (2H, t, J=5.4Hz), 6.46 (1H, d, J=2.4 Hz), 6.83 (1H, d, J=7.8 Hz), 7.13-7.22 (2H, m),7.33-7.39 (1H, m), 7.59-7.63 (1H, m), 7.80-7.85 (2H, m), 8.46 (1H, d,J=2.4 Hz), 8.88-8.90 (1H, m), 9.27 (2H, br), 1H not detected.

melting point 196-200° C.

Example 281-[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(216 mg), the title compound was obtained as colorless crystals (yield81 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.49-2.51 (3H, m), 4.00 (2H, t, J=6.0Hz), 6.47 (1H, d, J=2.1 Hz), 6.85-6.90 (1H, m), 6.98-7.12 (2H, m),7.61-7.65 (1H, m), 7.81-7.88 (2H, m), 8.51 (1H, d, J=2.7 Hz), 8.89-8.91(1H, m), 9.29 (2H, br), 1H not detected.

Example 29N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(200 mg), the title compound was obtained as colorless crystals (yield125 mg, 67%). More specifically, tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(200 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid(1 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was basified by addingdropwise to a 6% aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free salt of the title compound as a pale-yellow oil. Theobtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-ethanol to give the title compound ascolorless crystals (yield 125 mg, 67%).

¹H-NMR (DMSO-d₆) δ: 1.71 (3H, s), 2.49-2.51 (3H, m), 3.98 (2H, t, J=5.7Hz), 6.49 (1H, d, J=2.1 Hz), 7.16-7.23 (2H, m), 7.58-7.62 (1H, m),7.79-7.86 (2H, m), 8.50-8.51 (1H, m), 8.87-8.89 (1H, m), 9.30 (2H, br),1H not detected.

melting point 178-181° C.

Example 303-[4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl]benzonitrilehydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(298 mg), the title compound was obtained as colorless crystals (yield132 mg, 52%).

¹H-NMR (DMSO-d₆) δ: 2.48-2.51 (3H, m), 3.98 (2H, brs), 6.65 (1H, d,J=1.8 Hz), 7.51-7.65 (4H, m), 7.85-7.95 (3H, m), 8.55 (1H, d, J=2.4 Hz),8.88-8.90 (1H, m), 9.25 (2H, br).

Example 311-[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(171 mg), the title compound was obtained as colorless crystals (yield74 mg, 46%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, br), 4.01 (2H, t, J=6.0 Hz), 5.40 (1H,br), 6.55 (1H, d, J=2.1 Hz), 7.13-7.16 (1H, m), 7.35-7.40 (1H, m),7.47-7.51 (2H, m), 7.61-7.65 (1H, m), 7.84-7.93 (2H, m), 8.57 (1H, d,J=2.1 Hz), 8.89-8.91 (1H, m), 9.23 (2H, br).

Example 321-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(110 mg), the title compound was obtained as colorless crystals (yield58 mg, 56%).

¹H-NMR (DMSO-d₆) δ: 2.48-2.51 (3H, m), 3.98 (2H, t, J=5.7 Hz), 6.62 (1H,d, J=1.8 Hz), 7.13-7.17 (2H, m), 7.28-7.36 (1H, m), 7.62-7.66 (1H, m),7.86-7.95 (2H, m), 8.61 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 9.31 (2H,br), 1H not detected.

Example 331-[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(105 mg), the title compound was obtained as colorless crystals (yield39 mg, 43%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.51 (3H, m), 3.99 (2H, brs), 6.62 (1H, d,J=1.8 Hz), 7.00-7.06 (1H, m), 7.27-7.44 (2H, m), 7.63-7.67 (1H, m), 7.86(1H, br), 7.94-7.97 (1H, m), 8.65 (1H, d, J=2.7 Hz), 8.90-8.92 (1H, m),9.08 (2H, m).

Example 341-[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

By a similar operation as in Example 26 and using tert-butyl{[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(103 mg), the title compound was obtained as colorless crystals (yield32 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 2.47-2.52 (3H, m), 3.97 (2H, t, J=6.0 Hz), 5.10 (1H,br), 6.64 (1H, brs), 7.15 (1H, t, J=7.8 Hz), 7.34-7.36 (1H, m),7.50-7.53 (1H, m), 7.62-7.67 (1H, m), 7.88 (1H, brs), 7.95-7.98 (1H, m),8.64 (1H, d, J=2.4 Hz), 8.90 (1H, d, J=4.8 Hz), 9.33 (2H, br).

Example 351-[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

tert-Butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(280 mg) was dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (6 mL) was added, and the mixture wasstirred at room temperature for 16 hr. The reaction solution wasbasified by adding dropwise to a 6% aqueous sodium hydrogencarbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: ethylacetate-hexane=1:1→9:1) to give a free salt of the title compound as apale-yellow oil. The obtained free salt was dissolved in ethyl acetate,a 4 mol/L hydrogen chloride-ethyl acetate solution was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate and hexane, and recrystallized fromethyl acetate-ethanol to give the title compound as colorless crystals(yield 84 mg, 35%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.51 (3H, m), 3.97 (2H, s), 6.57 (1H, d, J=1.8Hz), 6.98-7.02 (2H, m), 7.27-7.33 (1H, m), 7.40-7.47 (1H, m), 7.58-7.62(1H, m), 7.80-7.87 (2H, m), 8.54 (1H, d, J=2.7 Hz), 8.86-8.88 (1H, m),9.06 (2H, br).

Example 361-[5-(2-fluorophenyl)-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

A suspension of tert-butyl{[5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(369 mg), (2-fluorophenyl)boronic acid (234 mg), sodium carbonate (265mg) and tetrakis(triphenylphosphine)palladium (48.9 mg) in1,2-dimethoxyethane (15 mL) and water (7.5 mL) was stirred at 105° C.for 12 hr. The reaction mixture was allowed to cool to room temperature,water was added and the mixture was extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=1:4) to give an oil. The obtained oil was dissolved in ethanol(5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) wasadded, and the mixture was stirred at room temperature for 4 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was neutralized by adding a saturated aqueous sodiumhydrogencarbonate solution (50 mL). The mixture was extracted with ethylacetate, and the extract was washed with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluent: ethyl acetate), and further by HPLC (ODS, 0.1%trifluoroacetic acid-containing water-0.1% trifluoroaceticacid-containing acetonitrile=9:1-0.1% trifluoroacetic acid-containingacetonitrile) to give trifluoroacetate of the title compound. Theobtained trifluoroacetate was neutralized with a saturated aqueoussodium hydrogencarbonate solution, and the mixture was extracted withethyl acetate. The extract was washed successively with a saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure to give a free salt of the title compound (yield65 mg). The free salt (62 mg) was dissolved in ethyl acetate (2 mL), asolution of fumaric acid (17 mg) in methanol (2 mL) was added, and themixture was stirred for 10 min. The reaction mixture was concentratedunder reduced pressure, and the residue was recrystallized from ethanolto give the title compound as white crystals (yield 25 mg, 7%).

¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 2.40 (3H, s), 3.75 (2H, s), 6.46 (3H,s), 7.20-7.28 (3H, s), 7.44-7.52 (1H, m), 7.63-7.67 (1H, m), 7.88-7.92(1H, m), 8.61 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 3H not detected.

Example 37N-methyl-1-(5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrol-3-yl)methanaminehydrochloride

To a solution of5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde(137 mg) in absolute tetrahydrofuran (5 mL) was added at roomtemperature, a 2 mol/L solution (0.36 mL) of methylamine intetrahydrofuran was added, and the mixture was stirred for 16 hr. Sodiumborohydride (27 mg) and methanol (2 mL) were added, and the mixture wasstirred at the same temperature for 2 min. A saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (5 mL), di-tert-butyl bicarbonate (218 mg), water (2 mL)and sodium hydrogencarbonate (84 mg) were added, and the mixture wasstirred at room temperature for 30 min. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL), manganese dioxide (75% chemically treatedproduct, 1.0 g) was added, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was filtered through celite,and celite was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=19:1-1:1), fractionscontaining a material showing Rf value of 0.46 (eluent:hexane-ethylacetate=3:1) by TLC analysis were collected and concentrated underreduced pressure. The residue was dissolved in ethanol (1 mL), and a 4mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. Afterstirring at room temperature for 2 hr, the solvent was evaporated underreduced pressure. The residue was purified by HPLC (ODS, 0.1%trifluoroacetic acid-containing water-0.1% trifluoroaceticacid-containing acetonitrile=97:3→0.1% trifluoroacetic acid-containingacetonitrile) to give trifluoroacetate of the title compound. Theobtained trifluoroacetate was neutralized with a saturated aqueoussodium hydrogencarbonate solution, extracted with ethyl acetate, washedsuccessively with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine and dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved inethyl acetate (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution(1 mL) was added, and the mixture was concentrated under reducedpressure. Recrystallization from ethanol gave the title compound (yield23 mg, 15%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.97 (2H, s), 6.49 (1H, s), 7.13-7.15(2H, m), 7.37-7.48 (3H, m), 7.80-7.87 (2H, m), 8.72 (2H, br), 8.86 (1H,s), 9.33 (1H, s).

Example 38N-methyl-1-{1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

By a similar reaction as in Example 12 and using1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(180 mg), the title compound was obtained as a solid (yield 110 mg,48%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.53-2.57 (3H, m), 4.02-4.10 (2H, m),6.51 (1H, d, J=1.8 Hz), 7.01 (2H, d, J=6.9 Hz), 7.11-7.35 (4H, m),7.44-7.46 (1H, m), 7.84 (1H, d, J=2.1 Hz), 8.61-8.62 (1H, m), 9.07 (2H,br), 1H not detected.

Example 391-[5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

5-(2,6-Difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(250 mg) was added to a mixture of a 40% methylamine methanol solution(560 mg) and methanol (5 mL) at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (41 mg) was added to the reactionmixture and the mixture was stirred for 10 min. The reaction mixture wasconcentrated under reduced pressure at 30° C. The residue was extractedwith a saturated aqueous sodium hydrogencarbonate solution and ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent: ethyl acetate), dissolved in ethanol (5 mL), and a solution offumaric acid (84 mg) in ethanol (5 mL) was added to allowcrystallization to give the title compound as colorless crystals (yield229 mg, 67%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.85 (2H, s), 6.48 (2H, s), 6.57 (1H,d, J=1.7 Hz), 7.12-7.18 (2H, m), 7.55-7.66 (2H, m) 7.81 (1H, d, J=1.7Hz), 7.93-7.97 (1H, m), 8.61 (1H, d, J=2.1 Hz), 8.90 (1H, dd, J=4.7, 1.5Hz), 3H not detected.

Example 401-[5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

To a solution of5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(0.78 g) in methanol (20 mL) were added methylammonium chloride (1.61 g)and sodium cyanoborohydride (0.49 g), and the mixture was stirred atroom temperature for 16 hr. The reaction mixture was concentrated underreduced pressure, a saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent: hexane-ethyl acetate=3:2→0:1) to give an oil (0.39 g). The oilwas dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethylacetate solution (1.5 mL) was added, and the mixture was concentratedunder reduced pressure. Crystallization from methanol-ethyl acetate gavethe title compound as crystals (yield 0.41 g, 43%).

¹H-NMR (DMSO-d₆) δ: 1.20-1.46 (5H, m), 1.68-1.88 (5H, m), 2.45-2.59 (1H,m), 2.48 (3H, s), 3.97 (2H, d, J=5.3 Hz), 6.48 (1H, s), 7.04 (2H, d,J=8.1 Hz), 7.20 (2H, d, J=8.1 Hz), 7.51-7.57 (1H, m), 7.73-7.79 (2H, m),8.43 (1H, s), 8.83 (1H, d, J=4.7% Hz), 9.17 (2H, s), 1H not detected.

Example 411-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

By a similar reaction as in Example 12 and using4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(121 mg), the title compound was obtained as a colorless solid (yield30.7 mg, 20%). More specifically,4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(121 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution(0.22 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 4 hr. A solution (2 mL) of sodiumborohydride (28 mg) in methanol was added to the reaction mixture, andthe mixture was stirred at room temperature for 20 min. A aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate→ethyl acetate-methanol=1:4) to give a free salt of the titlecompound. To a solution (2 mL) of the obtained free salt in ethanol wasadded a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). Afterallowing to stand at room temperature for 30 min, the mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol to give the title compound as a colorless solid (yield 30.7mg, 20%).

¹H-NMR (DMSO-d₆) δ: 2.56-2.59 (3H, m), 4.03-4.05 (2H, m), 7.14-7.16 (2H,m), 7.41-7.48 (3H, m), 7.53-7.62 (1H, m), 7.80-7.85 (2H, m), 8.50 (1H,d, J=2.4 Hz), 8.88-8.89 (1H, m), 9.07 (2H, br), 1H not detected.

melting point 201-203° C.

Example 421-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution(0.8 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 2 hr. Sodium borohydride (91 mg) andmethanol (7 mL) were added, and the mixture was stirred at the sametemperature for further 30 min. The reaction mixture was concentratedunder reduced pressure. A saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (hexane-ethyl acetate=19:1→0:1). Theabove-mentioned operation was repeated to give the title compound (0.22g, yield 39%) as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 3.63 (2H, s), 7.22-7.42 (7H, m),7.56-7.60 (1H, m), 8.55 (1H, d, J=2.1 Hz), 8.73 (1H, dd, J=4.8, 1.8 Hz),1H not detected.

melting point 98-99° C.

Example 431-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine0.5 fumarate

1-[4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine(32 mg) was dissolved in ethanol (2 mL), fumaric acid (10 mg) was added,and the mixture was stood at room temperature for 1 hr. The precipitatewas collected by filtration to give the title compound as a colorlesssolid (yield 16 mg, 42%).

¹H-NMR (DMSO-d₆) δ: 2.30 (3H, s), 3.60 (2H, s), 6.50 (1H, s), 7.18-7.21(2H, m), 7.39-7.50 (4H, m), 7.57-7.61 (1H, m), 7.79-7.83 (1H, m), 8.50(1H, d, J=2.1 Hz), 8.87 (1H, dd, J=5.1, 1.8 Hz), 2H not detected.

melting point 163-166° C.

Example 441-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminedihydrochloride

By a similar reaction as in Example 12 and using5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde(134 mg), the title compound was obtained as a colorless solid (yield96.1 mg, 57%). More specifically,5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde(134 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution(0.6 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 4 hr. A solution (5 mL) of sodiumborohydride (76 mg) in methanol was added to the reaction mixture, andthe mixture was stirred at room temperature for 20 min. An aqueoussodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate→ethyl acetate-methanol=1:4) togive a free salt of the title compound. To a solution (2 mL) of theobtained free salt in ethanol was added a 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL). After allowing to stand at roomtemperature for 30 min, the mixture was concentrated under reducedpressure, and the residue was recrystallized from ethanol to give thetitle compound as a colorless solid (yield 96.1 mg, 57%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.56 (6H, m), 3.97-4.02 (2H, m), 6.55 (1H, d,J=1.8 Hz), 7.08-7.11 (1H, m), 7.22-7.26 (2H, m), 7.47-7.60 (2H, m),7.76-7.82 (2H, m), 8.44 (1H, d, J=2.4 Hz), 9.04 (2H, br), 1H notdetected.

melting point 212-213° C.

Example 451-[5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

By a similar reaction as in Example 12 and using5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(183 mg), the title compound was obtained as a colorless solid (yield78.3 mg, 37%).

¹H-NMR (DMSO-d₆) δ: 2.54 (3H, s), 4.02 (2H, s), 6.52 (1H, d, J=2.1 Hz),7.00-7.04 (1H, m), 7.11-7.19 (2H, m), 7.46-7.51 (1H, m), 7.57-7.60 (1H,m), 7.74-7.78 (2H, m), 8.03-8.08 (1H, m), 8.70-8.85 (3H, m).

Example 461-{5-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

To a solution (3 mL) of5-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde(217 mg) in tetrahydrofuran were added a 40% methylamine methanolsolution (152 mg) and methanol (1 mL) at room temperature. Afterstirring at room temperature for 1 hr, sodium borohydride (82 mg) wasadded at 0° C. After stirring at room temperature for 30 min, water wasadded and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free salt of the title compound as a pale-yellow oil (yield152 mg). A solution of the obtained free salt in ethyl acetate (5 mL)was added to a solution of fumaric acid (50.6 mg) in methanol (1 mL),and the mixture was concentrated under reduced pressure. The residue wasrecrystallized from ethanol/water=95/5 to give the title compound ascolorless crystals (yield 143 mg, 48%).

¹H-NMR (DMSO-d₆) δ: 2.46 (3H, s), 3.82 (3H, s), 3.85 (2H, s), 6.41 (1H,d, J=1.8 Hz), 6.46 (2H, s), 7.15-7.26 (3H, m), 7.46-7.56 (3H, m), 8.11(1H, s), 3H not detected.

Example 47

N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

To a solution of5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(521 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) was added a 40%methylamine methanol solution (373 mg). After stirring at roomtemperature for 1 hr, sodium borohydride (202 mg) was added. Afterstirring at the same temperature for 30 min, water was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give afree salt of the title compound as a yellow oil (yield 422 mg). Asolution of the obtained free salt in ethanol (5 mL) was added to asolution (15 mL) of fumaric acid (144 mg) in ethanol, and the mixturewas concentrated under reduced pressure. The residue was recrystallizedfrom ethanol to give the title compound as colorless crystals (yield 414mg, 56%).

¹H-NMR (DMSO-d₆) δ: 1.81 (3H, s), 2.45 (3H, s), 3.88 (2H, s), 6.33 (1H,d, J=1.8 Hz), 6.46 (2H, s), 6.83-6.85 (1H, m), 7.12-7.22 (2H, m),7.32-7.37 (1H, m), 7.57-7.61 (1H, m), 7.69 (1H, d, J=1.8 Hz), 7.78-7.82(1H, m), 8.44-8.45 (1H, m), 8.87-8.89 (1H, m), 3H not detected.

melting point 207-210° C.

Example 481-[4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(429 mg) in tetrahydrofuran (5 mL) and methanol (3 mL) was added a 40%methylamine methanol solution (275 mg) at room temperature. Afterstirring for 30 min, sodium borohydride (99 mg) was added. Afterstirring at the same temperature for 1 hr, water was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give afree salt of the title compound as a yellow oil (yield 257 mg). Asolution of the obtained free salt in ethyl acetate (5 mL) was added toa solution (10 mL) of fumaric acid (79 mg) in methanol, and the mixturewas concentrated under reduced pressure. The residue was recrystallizedfrom ethanol to give the title compound as colorless crystals (yield 216mg, 36%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.75 (2H, s), 6.54 (2H, s), 7.13-7.19(1H, m), 7.24-7.32 (2H, m), 7.55-7.66 (2H, m), 7.81 (1H, s), 7.88-7.92(1H, m), 8.56-8.57 (1H, m), 8.90-8.92 (1H, m), 3H not detected.

Example 491-[4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)pyrrole-3-carbaldehyde(0.60 g) in tetrahydrofuran (6 mL) and methanol (6 mL) was added a 40%methylamine methanol solution (1.8 mL) and the mixture was stirred atroom temperature for 30 min. Sodium borohydride (84 mg) was added atroom temperature and the mixture was stirred for 5 min and concentratedunder reduced pressure. A saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate) to give a free salt of the title compound as apale-yellow oil (yield 0.36 g). The obtained free salt (0.36 g) wasdissolved in ethanol (10 mL), and a solution of fumaric acid (0.12 g) inethanol (10 mL) was added at room temperature. The reaction mixture wasstirred for 14 hr, and concentrated under reduced pressure. The residuewas recrystallized from ethanol to give the title compound as colorlesscrystals (yield 0.73 g, 43%).

¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 3.69 (2H, s), 6.54 (2H, s), 7.21-7.32(3H, m), 7.54-7.65 (3H, m), 7.86-7.90 (1H, m), 8.57 (1H, d, J=2.4 Hz),8.89-8.91 (1H, m), 3H not detected.

Example 501-[4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution (5 mL) of4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)pyrrole-3-carbaldehyde(0.45 g) in tetrahydrofuran were added a 40% methylamine methanolsolution (1.5 mL) and methanol (5 mL) and the mixture was stirred atroom temperature for 30 min. Sodium borohydride (76 mg) was added atroom temperature and the mixture was stirred for 30 min and concentratedunder reduced pressure. A saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate) to give a free salt of the title compound as apale-yellow oil (yield 0.33 g). The obtained free salt (0.33 g) wasdissolved in ethanol (4 mL), and a solution of fumaric acid (0.10 g) inethanol (10 mL) was added at room temperature. After stirring for 30min, the reaction mixture was concentrated under reduced pressure. Theresidue was recrystallized from ethanol to give the title compound ascolorless crystals (yield 0.32 g, 54%).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 2.43 (3H, s), 3.80 (2H, s), 6.52 (2H,s), 6.97-6.99 (1H, m), 7.19-7.26 (2H, m), 7.37-7.42 (1H, m), 7.58-7.65(2H, m), 7.80-7.84 (1H, m), 7.46 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m),3H not detected.

Example 511-[2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(160 mg) was added to a mixture of 40% methylamine methanol solution(325 mg) and methanol (20 mL) at room temperature. After stirring for 30min, sodium borohydride (48 mg) was added and the mixture was stirredfor 1 hr. The reaction mixture was concentrated under reduced pressureat 30° C. The residue was extracted with a saturated aqueous sodiumhydrogencarbonate solution and ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3) anddissolved in ethanol (2 mL), and a solution of fumaric acid (48 mg) inethanol (2 mL) was added. Crystallization from the mixture gave thetitle compound as colorless crystals (yield 29 mg, 14%).

¹H-NMR (DMSO-d₆) δ: 2.28 (3H, s), 3.65 (2H, s), 6.51 (2H, s), 6.73 (1H,s), 7.21-7.28 (2H, m), 7.55-7.65 (1H, m), 7.73-7.77 (1H, m), 8.08-8.12(1H, m), 8.82 (1H, d, J=2.4 Hz), 8.96 (1H, dd, J=4.9, 1.5 Hz), 3H notdetected.

Example 521-[2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of methylamine hydrochloride (232 mg) in methanol (10 mL)was added2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(250 mg) and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (218 mg) was added and the mixture was stirred for2 hr. The reaction mixture was concentrated under reduced pressure at30° C. and extracted with a saturated aqueous sodium hydrogencarbonatesolution and ethyl acetate. The extract was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate-methanol=1:0→17:3) and dissolved in ethyl acetate(10 mL), and a solution of fumaric acid (80 mg) in methanol (2 mL) wasadded. Crystallization from the mixture gave the title compound ascolorless crystals (yield 97 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.23 (3H, s), 3.61 (2H, s), 6.51 (2H, s), 6.61 (1H,s), 7.27-7.33 (2H, m), 7.43-7.56 (2H, m), 7.69-7.74 (1H, m), 8.02-8.06(1H, m), 8.80 (1H, brs), 8.94 (1H, dd, J=4.8, 1.4 Hz), 3H not detected.

Example 531-{1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

tert-Butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(120 mg) was dissolved in ethanol (3 mL), and a 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL) was added. After stirring at roomtemperature for 4 hr, the mixture was concentrated under reducedpressure, and the residue was recrystallized from ethanol to give thetitle compound as a solid (yield 51.3 mg, 49%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.96 (2H, m), 6.51 (1H, s), 7.15-7.17(2H, m), 7.39-7.50 (3H, m), 7.77 (1H, s), 7.84 (1H, s), 8.48 (1H, s),8.89 (2H, br), 9.03 (1H, s).

Example 545-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinonitrilehydrochloride

A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(112 mg), zinc cyanide (50 mg) and N,N-dimethylformamide (4 mL) wasdegassed with argon gas. Tetrakis(triphenylphosphine)palladium (46 mg)was added, and the mixture was stirred at 100° C. for 1.5 hr. Aftercooling the reaction mixture to room temperature, a saturated aqueoussodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give acolorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. Afterstirring at room temperature for 1 hr, the mixture was concentratedunder reduced pressure, and recrystallized from ethanol to give thetitle compound as a solid (yield 32.7 mg, 42%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.52 (3H, m), 3.98 (2H, s), 6.50 (1H, s),7.13-7.16 (2H, m), 7.37-7.50 (3H, m), 7.76 (1H, d, J=1.8 Hz), 8.28 (1H,d, J=2.1 Hz), 8.66 (1H, d, J=2.4 Hz), 8.82 (2H, br), 9.31 (1H, d, J=2.1Hz).

Example 55 methyl5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinatehydrochloride

A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(112 mg), dichloro[bis(triphenylphosphine)]palladium (28 mg),triethylamine (0.25 mL) and methanol (15 mL) was stirred under a carbonmonoxide atmosphere (3 atm) at 100° C. for 12 hr. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. A saturated aqueous sodium hydrogencarbonate solution wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→3:2) to give a colorless oil. The obtained oil wasdissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethylacetate solution (2 mL) was added. After stirring at room temperaturefor 1 hr, the mixture was concentrated under reduced pressure, andrecrystallized from ethanol to give the title compound as a solid (yield47.0 mg, 56%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.51 (3H, m), 3.91 (3H, s), 3.98 (2H, s), 6.50(1H, d, J=1.8 Hz), 7.15-7.17 (2H, m), 7.37-7.50 (3H, m), 7.80 (1H, s),7.93-7.94 (1H, m), 8.81 (1H, d, J=2.1 Hz), 8.91 (2H, br), 9.29 (1H, d,J=2.1 Hz).

Example 56N-methyl-1-{1-[(5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

Under an argon atmosphere, a mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(112 mg), methylboronic acid (18 mg),tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138mg) and 1,4-dioxane (5 mL) was stirred at 80° C. for one day. Thereaction mixture was poured into a saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→1:1) to give an oil. The oil was dissolved in ethanol (1mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) wasadded. After stirring at room temperature for 1 hr, the mixture wasconcentrated under reduced pressure. The residue was recrystallized fromethanol-ethyl acetate to give the title compound as a colorless solid(yield 32.6 mg, 39%).

¹H-NMR (DMSO-d₆) δ: 2.28 (3H, s), 2.50-2.53 (3H, m), 3.94-4.00 (2H, m),6.48 (1H, d, J=1.8 Hz), 7.12-7.15 (2H, m), 7.37-7.52 (4H, m), 7.75 (1H,s), 8.29 (1H, d, J=2.1 Hz), 8.70 (1H, d, J=1.5 Hz), 9.08 (2H, br), 1Hnot detected.

Example 571-[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

By a similar operation as in Example 33 and using tert-butyl{[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(177 mg), the title compound was obtained as colorless crystals (yield68 mg, 45%).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 2.32 (3H, s), 2.49 (3H, s), 3.99 (2H,s), 6.38 (1H, d, J=1.8 Hz), 6.71 (1H, d, J=8.1 Hz), 6.95-7.03 (2H, m),7.59-7.63 (1H, m), 7.77-7.85 (2H, m), 8.48 (1H, d, J=2.7 Hz), 8.88-8.90(1H, m), 9.07 (2H, br).

Example 58N-methyl-1-{5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methanaminedihydrochloride

To a solution of tert-butyl methyl{[5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(275 mg) in ethyl acetate (2 mL) was added a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL), and the mixture was stirred atroom temperature for 4 hr. The precipitated crystals were collected byfiltration, washed with ethyl acetate and recrystallized from ethanol togive the title compound as white crystals (yield 157 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.29 (3H, s), 3.98 (2H, t, J=5.6 Hz),6.67 (1H, d, J=1.9 Hz), 7.48 (2H, d, J=8.7 Hz), 7.60 (1H, dd, J=8.6, 4.4Hz), 7.86-7.97 (4H, m), 8.59 (1H, d, J=1.9 Hz), 8.88 (1H, dd, J=4.8, 1.4Hz), 9.20 (2H, s), 1H not detected.

Example 59(2-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl}phenyl)methanolfumarate

tert-Butyl({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate(132 mg) was dissolved in trifluoroacetic acid (1 mL), and the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasbasified with a saturated aqueous sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: ethylacetate-methanol=1:0→9:1) to give a free salt of the title compound as acolorless oil (yield 60.3 mg). A solution of the obtained free salt inethyl acetate (5 mL) was added to a solution of fumaric acid (19.6 mg)in methanol (2 mL), and the mixture was concentrated under reducedpressure. The residue was recrystallized from ethanol to give the titlecompound as colorless crystals (yield 48 mg, 35%).

¹H-NMR (DMSO-d₆) δ: 2.42 (3H, s), 3.83 (2H, s), 4.00 (2H, s), 6.35 (1H,d, J=1.5 Hz), 6.46 (2H, s), 6.81-6.83 (1H, m), 7.17-7.22 (1H, m),7.41-7.50 (2H, m), 7.55-7.60 (1H, m), 7.65 (1H, s), 7.75-7.78 (1H, m),8.46 (1H, d, J=2.4 Hz), 8.86 (1H, d, J=4.8 Hz), 4H not detected.

Example 60 N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine fumarate

By a similar reaction as in Example 59 and using tert-butyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(943 mg), the title compound was obtained as colorless crystals (yield553 mg, 57%). More specifically, tert-butyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(943 mg) was dissolved in trifluoroacetic acid (3 mL), and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasbasified with a saturated aqueous sodium hydrogencarbonate solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: hexane-ethylacetate=1:9) to give a free salt of the title compound as a colorlessoil (yield 631 mg). A solution of the obtained free salt in ethylacetate (5 mL) was added to a solution of fumaric acid (211 mg) inmethanol (2 mL), and the mixture was concentrated under reducedpressure. The residue was recrystallized from ethanol-water to give thetitle compound as colorless crystals (yield 553 mg, 57%).

¹H-NMR (DMSO-d₆) δ: 1.71 (3H, s), 2.42 (3H, s), 3.83 (2H, s), 6.34 (1H,d, J=1.8 Hz), 6.45 (2H, s), 7.15-7.16 (1H, m), 7.21-7.22 (1H, m),7.56-7.60 (1H, m), 7.64-7.65 (1H, m), 7.78-7.82 (1H, m), 8.48 (1H, d,J=2.4 Hz), 8.84-8.86 (1H, m), 3H not detected.

melting point 182-183° C.

Example 61N-methyl-1-(5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanaminefumarate

5-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (650 mg) wasdissolved in a mixture of a 40% methylamine methanol solution (808 mg)and methanol (30 mL) at room temperature and the mixture was stirred for10 min. Sodium borohydride (118 mg) was added and the mixture wasstirred for 10 min. The reaction mixture was concentrated under reducedpressure at 30° C. and the residue was extracted with a saturatedaqueous sodium hydrogencarbonate solution (40 mL) and ethyl acetate (80mL). The extract was washed with saturated brine (40 mL), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent: ethyl acetate) and a solution of fumaric acid (242 mg) inethanol (24 mL) was added. The obtained crystals were collected byfiltration and recrystallized from ethanol-water (85:15) to give thetitle compound as colorless crystals (yield 480 mg, 52%).

¹H-NMR (DMSO-d₆) δ: 2.42 (3H, s), 3.86 (2H, s), 6.42 (1H, d, J=1.9 Hz),6.47 (2H, s), 7.14-7.18 (2H, m), 7.34-7.46 (3H, m), 7.54-7.58 (1H, m),7.67 (1H, d, J=1.9 Hz), 7.76-7.80 (1H, m), 8.46 (1H, dd, J=2.5, 0.8 Hz),8.84 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.

Example 621-[5-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of5-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.37 g) intetrahydrofuran (15 mL) was added dropwise a solution of a 40%methylamine methanol solution (0.41 g) in tetrahydrofuran (1 mL) underice-cooling, and the mixture was stirred at room temperature for 2 hr.Methanol (10 mL) was added, and the mixture was further stirred at roomtemperature for 2 hr. Sodium borohydride (0.06 g) was gradually addedunder ice-cooling, and the mixture was stirred at room temperature for 1hr. The reaction mixture was concentrated under reduced pressure, asaturated aqueous sodium hydrogencarbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→ethyl acetate-methanol=5:1) to give a free salt of the titlecompound as a pale-brown oil. To a solution of the obtained free salt inethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.14g) in methanol (2.5 mL) under ice-cooling, and the mixture was stirredat room temperature for 15 min. The precipitate was collected byfiltration and recrystallized from ethanol-water to give the titlecompound as white crystals (yield 0.32 g, 61%).

¹H-NMR (DMSO-d₆) δ: 1.58 (6H, s), 2.28 (3H, s), 2.44 (3H, s), 3.87 (2H,s), 6.21 (1H, s), 6.45 (2H, s), 6.83 (2H, s), 7.60 (1H, dd, J=8.1, 1.8Hz), 7.70 (1H, s), 7.84 (1H, dd, J=8.4, 1.8 Hz), 8.46 (1H, s), 8.88 (1H,d, J=3.9 Hz), 3H not detected.

Example 63N-methyl-1-{5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methanaminefumarate

To a solution (3 mL) of5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(170 mg) in tetrahydrofuran were added a 40% methylamine methanolsolution (110 mg) and methanol (1 mL) at room temperature, and themixture was stirred for 1 hr. Sodium borohydride (59.8 mg) was addedunder ice-cooling. After stirring at room temperature for 2 hr, waterwas added and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→1:9) to give a free salt of the title compound as acolorless oil. The obtained free salt was dissolved in ethyl acetate,and added to a solution (1 mL) of fumaric acid (33.2 mg) in methanol.The solvent was evaporated under reduced pressure, and the residue wasrecrystallized from ethanol to give the title compound as colorlesscrystals (yield 89.3 mg, 38%).

¹H-NMR (DMSO-d₆) δ: 2.11 (3H, s), 2.43 (3H, s), 3.86 (2H, s), 6.38 (1H,d, J=1.8 Hz), 6.46 (2H, s), 7.07-7.20 (3H, m), 7.41-7.46 (1H, m),7.53-7.58 (1H, m), 7.68 (1H, d, J=1.8 Hz), 7.79-7.83 (1H, m), 8.43 (1H,d, J=2.4 Hz), 8.82-8.84 (1H, m), 3H not detected.

Example 64N-methyl-1-{5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methanamine0.5 fumarate

By a similar operation as in Example 63 and using5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(72.0 mg), the title compound was obtained as colorless crystals (yield56.4 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 3.00 (3H, s), 3.71 (2H, s), 6.41 (1H,s), 6.48 (1H, d, J=1.5 Hz), 7.14-7.17 (1H, m), 7.61-7.65 (2H, m),7.70-7.80 (2H, m), 7.93-7.97 (1H, m), 8.02-8.05 (1H, m), 8.66 (1H, d,J=2.1 Hz), 8.87-8.89 (1H, m), 2H not detected.

Example 652-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl}benzonitrilefumarate

By a similar operation as in Example 63 and using2-[4-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-yl]benzonitrile (129mg), the title compound was obtained as colorless crystals (yield 69 mg,38%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.82 (2H, s), 6.47 (2H, s), 6.58 (1H,d, J=1.8 Hz), 7.34-7.36 (1H, m), 7.59-7.76 (4H, m), 7.84-7.89 (2H, m),8.53 (1H, d, J=2.4 Hz), 8.87-8.89 (1H, m), 3H not detected.

Example 661-[5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(0.42 g) in tetrahydrofuran (15 mL) was added dropwise a solution of a40% methylamine methanol solution (0.48 g) in tetrahydrofuran (1 mL)under ice-cooling, and the mixture was stirred at room temperature for 2hr. Methanol (10 mL) was added, and the mixture was further stirred atroom temperature for 2 hr. Sodium borohydride (0.07 g) was graduallyadded under ice-cooling, and the mixture was stirred at room temperaturefor 1% hr. The reaction mixture was concentrated under reduced pressure,a saturated aqueous sodium hydrogencarbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→ethyl acetate-methanol=5:1) to give a free salt of the titlecompound as a pale-brown oil. To a solution of the obtained free salt inethyl acetate (5 mL) was added dropwise a solution of fumaric acid (0.12g) in methanol (2 mL) under ice-cooling and the mixture was stirred atroom temperature for 15 min. The precipitate was collected byfiltration, and recrystallized from ethanol-water to give the titlecompound as white crystals (yield 0.18 g, 50%).

¹H-NMR (DMSO-d₆) δ: 1.62 (6H, s), 2.45 (3H, s), 3.88 (2H, s), 6.25 (1H,d, J=1.5 Hz), 6.45 (2H, s), 7.02 (2H, d, J=7.5 Hz), 7.24 (1H, d, J=7.5Hz), 7.58-7.62 (1H, m), 7.71 (1H, s), 7.81-7.85 (1H, m), 8.44 (1H, d,J=2.7 Hz), 8.89 (1H, dd, J=4.8, 1.5 Hz), 3H not detected.

Example 67N-methyl-1-{5-[2-(methylsulfinyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methanaminefumarate

To a suspension (5 mL) of sodium hydride (60% in oil, 39.5 mg) intetrahydrofuran were added a solution (3 mL) of5-[2-(methylsulfinyl)phenyl]-1H-pyrrole-3-carbaldehyde (160 mg) inN,N-dimethylformamide, 15-crown-5 (181 mg), and pyridin-3-ylsulfonylchloride (134 mg) under ice-cooling. After stirring at room temperaturefor 1 hr, water was added and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was suspended in tetrahydrofuran (5 mL), a 40% methylaminemethanol solution (160 mg) was added at room temperature and the mixturewas stirred for 1 hr. Sodium borohydride (86.5 mg) was added underice-cooling. After stirring at room temperature for 2 hr, water wasadded and the mixture was extracted twice with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→ethyl acetate) to give a free salt of the title compound asa pale-yellow oil. The obtained free salt was dissolved in ethylacetate, and added to a solution (1 mL) of fumaric acid (28.1 mg) inmethanol. The solvent was evaporated under reduced pressure, and theresidue was recrystallized from ethanol to give the title compound ascolorless crystals (yield 83.9 mg, 24%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 2.49-2.51 (3H, m), 3.81 (2H, s), 6.46(2H, s), 6.50 (1H, d, J=1.5 Hz), 7.00 (1H, br), 7.50-8.00 (6H, m), 8.57(1H, br), 8.87-8.89 (1H, m), 3H not detected.

Example 682-(2-fluorophenyl)-4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrilefumarate

2-(2-Fluorophenyl)-4-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile(295 mg) was dissolved in a solution of methylamine hydrochloride (1.12g) in methanol (20 mL) and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (1.06 g) was added and the mixture was stirred for2 hr. The reaction mixture was concentrated under reduced pressure at30° C., a saturated aqueous sodium hydrogencarbonate solution (40 mL)was added to the residue and the mixture was extracted with ethylacetate (80 mL). The extract was washed with saturated brine (40 mL),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: ethyl acetate-methanol=85:15→75:25), and then by basic silicagel column chromatography (eluent: ethyl acetate), and a solution offumaric acid (96 mg) in ethanol (5 mL) was added. Crystallization fromthe mixture gave the title compound as colorless crystals (yield 120 mg,30%).

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 3.76 (2H, s), 6.57 (2H, s), 7.28-7.37(3H, m), 7.63-7.71 (2H, m), 7.87 (1H, s), 7.95-7.99 (1H, m), 8.64 (1H,dd, J=2.5, 0.6 Hz), 8.94 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.

Example 695-(2-fluorophenyl)-3-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-carbonitrilefumarate

5-(2-fluorophenyl)-3-formyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-2-carbonitrile(650 mg) was dissolved in a mixture of a 40% methylamine methanolsolution (808 mg) and methanol (30 mL) at room temperature and themixture was stirred for 10 min. Sodium borohydride (118 mg) was addedand the mixture was stirred for 10 min. The reaction mixture wasconcentrated under reduced pressure at 30° C., a saturated aqueoussodium hydrogencarbonate solution (40 mL) was added to the residue andthe mixture was extracted with ethyl acetate (80 mL). The extract waswashed with saturated brine (40 mL), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: ethylacetate) and a solution of fumaric acid (242 mg) in ethanol (24 mL) wasadded. The obtained crystals were collected by filtration, andrecrystallized from ethanol-water (85:15) to give the title compound ascolorless crystals (yield 480 mg, 52%).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 3.74 (2H, s), 6.57 (2H, s), 6.71 (1H,s), 7.29-7.38 (3H, m), 7.58-7.64 (1H, m), 7.71-7.75 (1H, m), 7.96-8.00(1H, m), 8.66 (1H, d, J=2.3 Hz), 8.97 (1H, dd, J=4.9, 1.5 Hz), 3H notdetected.

Example 704-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}benzonitrilefumarate

To a solution (2 mL) of tert-butyl{[5-(4-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(382 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethylacetate solution (3 mL) at room temperature. The mixture was stirred for3 hr, and basified with a saturated aqueous sodium hydrogencarbonatesolution. The mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free salt of the title compound as a pale-yellow oil. Theobtained free salt was dissolved in ethyl acetate, and added to asolution (2 mL) of fumaric acid (77.1 mg) in methanol. The solvent wasevaporated under reduced pressure, and the residue was recrystallizedfrom a mixed solvent of ethanol and water to give the title compound ascolorless crystals (yield 218 mg, 55%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 3.79 (2H, s), 6.47 (2H, s), 6.55 (1H,d, J=1.8 Hz), 7.40-7.44 (2H, m), 7.55-7.60 (1H, m), 7.70-7.71 (1H, m),7.81-7.87 (3H, m), 8.55-8.56 (1H, m), 8.84-8.86 (1H, m), 3H notdetected.

Example 714-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}benzonitrile0.5 fumarate

By a similar operation as in Example 70 and using tert-butyl{[5-(5-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg), the title compound was obtained as colorless crystals (yield37.1 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.34 (3H, s), 3.71 (2H, s), 6.44 (1H, s), 6.55 (1H,brs), 7.52 (1H, t, J=9.0 Hz), 7.60-7.68 (2H, m), 7.73-7.75 (1H, m),7.91-7.93 (1H, m), 8.03-8.08 (1H, m), 8.64% (1H, d, J=2.4 Hz), 8.88-8.90(1H, m), 2H not detected.

Example 721-[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

tert-Butyl{[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(475 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 30 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate, added to a solution (13 mL) of fumaricacid (116 mg) in methanol, and the obtained crystals were collected byfiltration to give the title compound as colorless crystals (yield 385mg, 78%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 3.71 (3H, s), 3.82 (2H, s), 6.47 (1H,d, J=1.9 Hz), 6.48 (2H, s), 6.57-6.60 (1H, m), 7.02-7.07 (1H, m),7.12-7.18 (1H, m), 7.60-7.64 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.89-7.93(1H, m), 8.60 (1H, d, J=2.3 Hz), 8.88 (1H, dd, J=4.9, 1.5 Hz), 3H notdetected.

Example 731-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}phenyl)ethanonefumarate

By a similar operation as in Example 70 and using tert-butyl{[5-(3-acetyl-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(118 mg), the title compound was obtained as colorless crystals (yield44.7 mg, 37%).

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 2.49-2.53 (3H, m), 3.80 (2H, m), 6.47(2H, s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.40 (2H, m), 7.59-7.64 (1H, m),7.73 (1H, d, J=1.8 Hz), 7.86-7.93 (2H, m), 8.60 (1H, d, J=2.7 Hz),8.87-8.89 (1H, m), 3H not detected.

Example 741-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a solution of tert-butyl{[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(2.48 g) in ethyl acetate (10 mL) and methanol (10 mL) was added a 4mol/L hydrogen chloride-ethyl acetate solution (20 mL) at roomtemperature. After stirring for 5 hr, the mixture was concentrated underreduced pressure. The residue was basified with a saturated aqueoussodium hydrogencarbonate solution and extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→1:9) to give a free salt of the title compound as apale-yellow oil. The obtained free salt was dissolved in ethyl acetate(10 mL) and added to a solution of (10 mL) fumaric acid (350 mg) inmethanol. The solvent was evaporated under reduced pressure and theresidue was recrystallized from a mixed solvent of ethanol and water togive the title compound as colorless crystals (yield 793 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.78 (2H, s), 6.48 (2H, s), 6.56 (1H,d, J=1.8 Hz), 7.40-7.44 (1H, m), 7.61-7.65 (1H, m), 7.72-7.79 (2H, m),7.89-7.93 (1H, m), 8.32-8.34 (1H, m), 8.62 (1H, d, J=1.8 Hz), 8.88-8.90(1H, m), 3H not detected.

melting point 183-184° C.

Example 751-[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

tert-Butyl{[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(60 mg) was dissolved in methanol (5 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (1.5 mL) was added and the mixture wasstirred at 70° C. for 30 min. The reaction mixture was concentratedunder reduced pressure and a saturated aqueous sodium hydrogencarbonatesolution was added. The mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (8 mL), a solution of fumaric acid (58 mg) inmethanol (2 mL) was added, and the obtained crystals were collected byfiltration to give the title compound as colorless crystals (yield 45mg, 72%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 3.78 (2H, s), 6.49 (2H, s), 6.64 (1H,d, J=1.5 Hz), 7.30-7.33 (1H, m), 7.62-7.66 (1H, m), 7.77 (1H, d, J=1.5Hz), 7.94-7.98 (1H, m), 8.49-8.51 (1H, m), 8.64 (1H, d, J=1.5 Hz), 8.69(1H, d, J=2.3 Hz), 8.90 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.

Example 761-[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

tert-Butyl{[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(280 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 30 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and concentrated underreduced pressure. The residue was dissolved in ethyl acetate (10 mL), asolution of fumaric acid (116 mg) in methanol (3 mL) was added, and theobtained crystals were collected by filtration to give the titlecompound as colorless crystals (yield 197 mg, 68%).

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 3.81 (2H, s), 6.49 (2H, s), 6.52 (1H,d, J=1.9 Hz), 7.47-7.52 (1H, m), 7.61-7.73 (3H, m), 7.90-7.94 (1H, m),8.50 (1H, dd, J=4.9, 1.9 Hz), 8.63-8.64 (1H, m), 8.90 (1H, dd, J=4.5,1.5 Hz), 3H not detected.

Example 771-[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine1.5 fumarate

tert-butyl{[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg) was dissolved in methanol (8 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 30 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: ethyl acetate-methanol=99:1→19:1) to give a freesalt of the title compound. The obtained free salt was dissolved inethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2mL) was added, and the obtained crystals were collected by filtration togive the title compound as colorless crystals (yield 60 mg, 52%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 3.83 (2H, s), 6.52 (3H, s), 6.58 (1H,d, J=1.5 Hz), 7.57-7.63 (2H, m), 7.75-7.78 (2H, m), 7.85-7.89 (1H, m),8.20 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.6 Hz), 8.88 (1H, dd, J=4.9, 1.5Hz), 4H not detected.

Example 781-[5-(6′-chloro-2,3′-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine0.5 fumarate

tert-Butyl{[5-(6′-chloro-2,3′-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg) was dissolved in ethanol (8 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 30 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: ethyl acetate-methanol=99:1→19:1) to give a freesalt of the title compound. The obtained free salt was dissolved inethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2mL) was added, and the obtained crystals were collected by filtration togive the title compound as colorless crystals (yield 61 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 3.69 (2H, s), 6.46 (1H, s), 6.58-6.59(1H, m), 7.57-7.62 (1H, m), 7.66-7.70 (2H, m), 7.83-7.88 (2H, m), 8.15(1H, d, J=8.3 Hz), 8.52 (1H, d, J=1.9 Hz), 8.57 (1H, d, J=2.3 Hz),8.60-8.61 (1H, m), 8.86 (1H, d, J=4.9 Hz), 9.18 (1H, d, J=2.3 Hz), 2Hnot detected.

Example 791-{5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

By a similar operation as in Example 24 and using tert-butyl({5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(289 mg), the title compound was obtained as colorless crystals (yield74.2 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 3.94 (3H, s), 3.99 (2H, s), 6.65 (1H,d, J=1.8 Hz), 6.99-7.02 (1H, m), 7.42-7.47 (1H, m), 7.73-7.80 (2H, m),7.84 (1H, d, J=1.8 Hz), 8.27-8.28 (1H, m), 8.34-8.36 (1H, m), 9.10 (2H,brs).

Example 80(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}phenyl)methanolfumarate

By a similar operation as in Example 70 and using tert-butyl({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate(238 mg), the title compound was obtained as colorless crystals (yield55.3 mg, 22%).

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 3.80 (2H, s), 4.49 (2H, s), 6.43 (1H,d, J=1.8 Hz), 6.47 (2H, s), 6.97-7.02 (1H, m), 7.17-7.22 (1H, m),7.54-7.62 (2H, m), 7.68 (1H, d, J=1.2 Hz), 7.84-7.88 (1H, m), 8.56 (1H,d, J=2.1 Hz), 8.86-8.88 (1H, m), 4H not detected.

Example 811-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}phenyl)ethanolfumarate

By a similar operation as in Example 70 and using tert-butyl({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate(318 mg), the title compound was obtained as colorless crystals (yield69.7 mg, 21%).

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, d, J=6.3 Hz), 2.40 (3H, s), 3.81 (2H, s),4.90 (1H, q, J=6.3 Hz), 6.43 (1H, d, J=1.8 Hz), 6.47 (2H, s), 6.94-7.00(1H, m), 7.16-7.22 (1H, m), 7.58-7.68 (3H, m), 7.84-7.87 (1H, m), 8.55(1H, d, J=2.7 Hz), 8.86-8.88 (1H, m), 4H not detected.

Example 821-[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

tert-Butyl{[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(475 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 20 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in ethanol (13 mL), fumaric acid (116 mg) was added, andthe obtained crystals were collected by filtration to give the titlecompound as colorless crystals (yield 310 mg, 63%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 3.82 (2H, s), 3.86 (3H, s), 6.45 (1H,d, J=1.7 Hz), 6.48 (2H, s), 6.58-6.63 (1H, m), 7.10-7.16 (1H, m),7.24-7.30 (1H, m), 7.59-7.63 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.86-7.90(1H, m), 8.58 (1H, dd, J=2.3, 0.7 Hz), 8.87-8.89 (1H, m), 3H notdetected.

Example 831-[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

tert-Butyl{[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 20 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The obtained organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was dissolved in ethanol (6 mL), fumaric acid (49 mg) wasadded, and the obtained crystals were collected by filtration to givethe title compound as colorless crystals (yield 53 mg, 51%).

¹H-NMR (DMSO-d₆) δ: 2.45 (3H, s), 3.44 (3H, s), 3.83 (2H, s), 6.36 (1H,d, J=1.5 Hz), 6.48 (2H, s), 6.79-6.86 (2H, m), 7.44-7.52 (1H, m),7.60-7.65 (1H, m), 7.70 (1H, d, J=1.5 Hz), 7.88-7.92 (1H, m), 8.56 (1H,d, J=1.9 Hz), 8.88 (1H, dd, J=4.7, 1.7 Hz), 3H not detected.

Example 841-{5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}-N-methylmethanaminefumarate

By a similar operation as in Example 70 and using tert-butyl({5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate(550 mg), the title compound was obtained as colorless crystals (yield313 mg, 62% for 2 steps).

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 3.78 (2H, s), 6.40 (1H, s), 6.47 (2H,s), 7.15-7.24 (4H, m), 7.32 (1H, t, J=73.5 Hz), 7.54-7.58 (1H, m), 7.62(1H, s), 7.77-7.80 (1H, m), 8.50 (1H, d, J=2.4 Hz), 8.84 (1H, d, J=4.5Hz), 3H not detected.

Example 85N-methyl-1-[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

tert-Butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(230 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL) was added and the mixture wasstirred at 70° C. for 20 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The obtained organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent: ethyl acetate-methanol (99:1→95:5) to give a free salt of thetitle compound. This was dissolved in ethyl acetate (8 mL), a solutionof fumaric acid (90 mg) in methanol (2 mL) was added, and the obtainedcrystals were collected by filtration to give the title compound ascolorless crystals (yield 115 mg, 48%).

¹H-NMR (DMSO-d₆) δ: 1.89 (3H, s), 2.43 (3H, s), 3.84 (2H, s), 6.45 (1H,d, J=1.9 Hz), 6.48 (2H, s), 7.29 (1H, d, J=4.9 Hz), 7.60-7.65 (1H, m),7.73 (1H, d, J=1.9 Hz), 7.81-7.85 (1H, m), 7.98 (1H, s), 8.47 (1H, d,J=4.9 Hz), 8.51 (1H, d, J=1.9 Hz), 8.90 (1H, dd, J=4.9, 1.5 Hz), 3H notdetected.

Example 86N-methyl-1-[5-(2-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

By a similar operation as in Example 70 and using tert-butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(278 mg), the title compound was obtained as colorless crystals (yield93 mg, 32%).

¹H-NMR (DMSO-d₆) δ: 2.00 (3H, s), 2.43 (3H, s), 3.83 (2H, s), 6.42 (1H,s), 6.47 (2H, s), 7.20-7.24 (1H, m), 7.28-7.31 (1H, m), 7.59-7.63 (1H,m), 7.70 (1H, s), 7.80-7.84 (1H, m), 8.49-8.51 (2H, m), 8.88-8.90 (1H,m), 3H not detected.

Example 871-{5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine0.5 fumarate

To a solution of tert-butyl({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(86 mg) in ethanol (2 mL) was added a 4 mol/L hydrogen chloride-ethylacetate solution (2 mL) at room temperature. The mixture was stirred for2 hr, and concentrated under reduced pressure. The residue was basifiedwith a saturated aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The extract was washedsuccessively with a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a free salt of the titlecompound as a pale-yellow oil. The obtained free salt was dissolved inethyl acetate (2 mL) and added to a solution (2 mL) of fumaric acid(11.3 mg) in ethanol, and the solvent was evaporated under reducedpressure. The residue was recrystallized from ethanol to give the titlecompound as colorless crystals (yield 14 mg, 18%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.56 (3H, s), 3.68 (2H, s), 6.44 (1H,s), 6.53 (1H, s), 7.41-7.50 (2H, m), 7.64 (1H, s), 7.74-7.81 (2H, m),8.34 (1H, s), 8.48 (1H, s), 2H not detected.

Example 881-[4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

4-Chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(320 mg) was dissolved in a solution of methylamine hydrochloride (591mg) in methanol (32 mL) and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (557 mg) was added and the mixture was stirred for3 hrs. The reaction mixture was concentrated under reduced pressure at30° C., a saturated aqueous sodium hydrogencarbonate solution was addedto the residue and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: ethylacetate-methanol=99:1→95:5) to give a free salt of the title compound.This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid(102 mg) in methanol (2 mL) was added, and the obtained crystals werecollected by filtration to give the title compound as colorless crystals(yield 52 mg, 12%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.70 (2H, s), 6.65 (2H, s), 7.48-7.53(1H, m), 7.63-7.68 (1H, m), 7.81 (1H, s), 7.84-7.96 (2H, m), 8.40-8.42(1H, m), 8.65 (1H, d, J=1.9 Hz), 8.93 (1H, dd, J=4.9, 1.5 Hz), 3H notdetected.

Example 89N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methanaminefumarate

By a similar operation as in Example 70 and using tert-butyl methyl{[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methyl}carbamate(315 mg), the title compound was obtained as colorless crystals (yield165 mg, 51%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.83 (2H, s), 6.47 (2H, s), 6.52 (1H,d, J=1.8 Hz), 7.07-7.12 (2H, m), 7.55-7.62 (2H, m), 7.70 (1H, d, J=1.8Hz), 7.84-7.88 (1H, m), 8.53-8.54 (1H, m), 8.83-8.85 (1H, m), 3H notdetected.

Example 90N-methyl-1-[5-(3-methylpyridin-2-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

By a similar operation as in Example 70 and using tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(229 mg), the title compound was obtained as colorless crystals (yield124 mg, 53%).

¹H-NMR (DMSO-d₆) δ: 2.18 (3H, s), 2.44 (3H, s), 3.86 (2H, s), 6.46 (2H,s), 6.52 (1H, d, J=1.8 Hz), 7.32-7.36 (1H, m), 7.66-7.74 (3H, m),8.17-8.21 (1H, m), 8.28-8.30 (1H, m), 8.87-8.90 (2H, m), 3H notdetected.

Example 912-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}benzonitrilefumarate

By a similar operation as in Example 70 and using tert-butyl{[5-(3-cyano-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(170 mg), the title compound was obtained as colorless crystals (yield96 mg, 74%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 3.80 (2H, s), 6.47 (2H, s), 6.59 (1H,d, J=1.5 Hz), 7.43-7.48 (1H, m), 7.52-7.57 (1H, m), 7.60-7.65 (1H, m),7.76 (1H, d, J=1.8 Hz), 7.89-7.93 (1H, m), 8.02-8.07 (1H, m), 8.59-8.60(1H, m), 8.89-8.91 (1H, m), 3H not detected.

Example 924-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}thiophene-3-carbonitrilefumarate

By a similar operation as in Example 70 and using tert-butyl{[5-(4-cyano-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(297 mg), the title compound was obtained as colorless crystals (yield155 mg, 50%).

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 3.84 (2H, s), 6.47 (2H, s), 6.56 (1H,d, J=2.1 Hz), 7.59-7.74 (1H, m), 7.67 (1H, d, J=3.0 Hz), 7.73-7.74 (1H,m), 7.86-7.90 (1H, m), 8.57-8.59 (2H, m), 8.87-8.89 (1H, m), 3H notdetected.

The structures of the compounds described in Reference Examples areshown in Tables 1-14.

TABLE 1

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 6 H

H CO₂Et Cl 7 H

H CO₂Et Cl 8 H

Me CO₂Me Cl 9 H

H CO₂Et H 10 H

H CO₂Et H 11 H

Me CO₂Me H 12 H

H CO₂Et H 13 H

H CH₂OH H 14 H

Me CH₂OH H 15 H

H CHO H 16 H

Me CHO H 17 H

H CHO H 18 H

H CHO H 19 H H H CO₂Me H 20 H H Me CO₂Me H 21 H H H CO₂Et Me 22 H Br HCO₂Me H

TABLE 2

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 23 H Br Me CO₂Me H 24 HBr H CO₂Et Me 36

H CO₂Et H 37

H CO₂Et H 38

H CO₂Et H 39

H CO₂Et H 40

H CO₂Et H 41

Br H CO₂Me H 42

Br Me CO₂Me H 43

H H CO₂Et Me 44

Br H CO₂Et Me 45

H CO₂Et Me 46

Br H CH₂OH H 47

H H CH₂OH Me 48

Br H CHO H 49

Br Me CHO H 50 H

Me CHO H

TABLE 3

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 51

H H CHO Me 52 H H H CHO Me 53

H H CHO Me 54

Br H CHO Me 55

H CHO H 56

H CHO H 57

H CHO H 58

H CHO H 59

H CHO H 60

H CHO H 61

H CHO Me 62

H CHO H 63

H CHO H 64

H CHO H 65

Me CHO H 66

Me CHO H

TABLE 4

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 67

Me CHO H 68

Me CHO H 69

Me CHO H 70

Me CHO H 71

Br H CH₂NHMe H 72

Br H

H 73 H Br H

H 74

Br H

H 75

H

H 76

H

H 77

H

H 78

H

H 79

H

H 80

H

H

TABLE 5

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 81

H

H 82

H

H 83

H

H 84

H

H 85

H

H 86 H

H

H 87 H

H

H 88 H

H

H 89

H

H 90

H

H 91

H

H 92

H

H 93

Br H

Me

TABLE 6

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 97 H

H CO₂Et Cl 98 H

H CO₂Me Cl 99 H

F CO₂Me Cl 100 H

H CO₂Et H 101 H

H CO₂Me H 102 H

F CO₂Me H 103 H

H CH₂OH H 104 H

H CH₂OH H 105 H

H CHO H 106 H

H CHO H 107 H H H CHO H 111 H

F H H 112 H Br H CHO H

TABLE 7

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 113 H

H CHO H 114 H

Cl CHO H 115 H

F CHO H 116 H

F CHO H 122

H CO₂Et H 123

H CO₂Et H 124

H CO₂Et H 125

F CO₂Me H 126

H CHO H 127

H CHO H 128

H CHO H

TABLE 8

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 129

F CHO H 130

H CHO H 131

H CHO H 132

H CHO H 133

H CHO H 134

H CHO H 135

H CHO H 136

H CHO H 137

Cl CHO H 138

F CHO H

TABLE 9

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 139

F CHO H 140

H CHO Cl 141

H CHO Cl 142

H

H 143

H

H 144

H

H 145

H

H 146

H

H

TABLE 10

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 147 H

H CHO H 148 H

H CHO H 149 H

H CHO H 150 H

H CHO H 151 H

H CHO H 152 H

I CHO H 153

H CHO H 154

H CHO H 155

H CHO H 156

H CHO H 157

H CHO H

TABLE 11

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 158

I CHO H 159

H CHO H 160

H CHO Br 161

CN CHO H 162

H CHO CN 163

Br H

H 164

H

H 165

H

H 166

H

H 167

H

H

TABLE 12

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 168

H

H 169

H

H 170

H

H 171

H

H 172

H

H 173

H

H 174

H

H 175

H

H 176

H

H 177

H

H 178

H

H

TABLE 13

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 180

H

H 181

H

H 183

H

H 187

Br H

H 188

H

H 189

H CHO H 190 H

H CHO H 191 H

Cl CHO H 192

Cl CHO H 194

H

H 196

H

H

TABLE 14

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 197

H

H 198

H

H 199

H

H 200

H

H

The structures of the compounds described in Examples are shown inTables 15-23.

TABLE 15

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 1

H H 2HCl 2

H H HCl 3

H H 2HCl 4

H H 2HCl 5

H H HCl 6

H Me 2HCl 7

H H 2HCl 8

H H

9

H H 2HCl 10

Me H 2HCl 11

Me H HCl 12

Me H 2HCl 13

Me H HCl 14

Me H HCl

TABLE 16

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 15

Me H CF₃COOH 16

Me H HCl 17

H H HCl 18

H H 19

H H 2HCl 20

H H

21

H H

22

H H HCl 23

H H HCl 24

H H 2HCl 25

H H HCl 26

H H 2HCl 27

H H 2HCl 28

H H 2HCl

TABLE 17

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 29

H H 2HCl 30

H H HCl 31

H H 2HCl 32

H H 2HCl 33

H H HCl 34

H H 2HCl 35

H H HCl 36

H Me

TABLE 18

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 37

H H HCl 38

H H 2HCl 39

H H

40

H H 2HCl 41

F H 2HCl 42

F H 43

F H

44

H H 2HCl 45

H H HCl 46

H H

47

H H

TABLE 19

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 48

Cl H

49

F H

50

F H

51

H Cl

52

H Cl

53

H H HCl 54

H H HCl 55

H H HCl 56

H H 2HCl 57

H H HCl

TABLE 20

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) addition salt 58

H H 2HCl 59

H H

60

H H

TABLE 21

Ex. No. R^(1c) R^(2c) R^(3c) R^(4c) R^(5c) addition salt 61

H CH₂NHMe H

62

H CH₂NHMe H

63

H CH₂NHMe H

64

H CH₂NHMe H

65

H CH₂NHMe H

66

H CH₂NHMe H

67

H CH₂NHMe H

68

CN CH₂NHMe H

69

H CH₂NHMe CN

70

H CH₂NHMe H

71

H CH₂NHMe H

TABLE 22

Ex. No. R^(1c) R^(2c) R^(3c) R^(4c) R^(5c) addition salt 72

H CH₂NHMe H

73

H CH₂NHMe H

74

H CH₂NHMe H

75

H CH₂NHMe H

76

H CH₂NHMe H

77

H CH₂NHMe H

78

H CH₂NHMe H

79

H CH₂NHMe H HCl 80

H CH₂NHMe H

81

H CH₂NHMe H

82

H CH₂NHMe H

TABLE 23

Ex. No. R^(1c) R^(2c) R^(3c) R^(4c) R^(5c) addition salt 83

H CH₂NHMe H

84

H CH₂NHMe H

85

H CH₂NHMe H

86

H CH₂NHMe H

87

H CH₂NHMe H

88

Cl CH₂NHMe H

89

H CH₂NHMe H

90

H CH₂NHMe H

91

H CH₂NHMe H

92

H CH₂NHMe H

Experimental Example 1 Proton Potassium—Adenosine Triphosphatase(H⁺,K⁺-ATPase) Inhibitory Activity Test

According to the method [Biochim. Biophys. Acta, 728, 31 (1983)] ofWallmark et al., a gastric mucous membrane microsomal fraction wasprepared from the stomach of swine. First, the stomach was removed,washed with tap water, immersed in 3 mol/L brine, and the surface of themucous membrane was wiped with a paper towel. The gastric mucousmembrane was detached, chopped, and homogenized in a 0.25 mol/Lsaccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/Ltris-hydrochloric acid using polytron (Kinematica). The obtainedhomogenate was centrifuged at 20,000×g for 30 min and the supernatantwas centrifuged at 100,000×g for 90 min. The precipitate was suspendedin 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/Lsaccharose solution containing 7.5% Ficoll, and centrifuged at 100,000×gfor 5 hr. The fraction containing the interface between the both layerswas recovered, and centrifugally washed with 0.25 mol/L saccharosesolution.

The obtained microsomal fraction was used as a proton,potassium—adenosine triphosphatase standard product.

To 40 μL of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride,10 mmol/L potassium chloride, 10 mmol/L valinomycin, pH=6.5) containing2.5 μg/mL (based on the protein concentration) of the enzyme standardproduct was added a test compound (5 μL) dissolved in a 10% aqueousdimethyl sulfoxide solution, and the mixture was incubated at 37° C. for30 min. The enzyme reaction was started by adding 5 μL of a 2 mmol/Ladenosine triphosphate tris salt solution (50 mmol/L HEPES-tris buffer(5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carriedout at 37° C. for 20 min, and 15 of a malachite green solution (0.12%malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammoniummolybdate and 11% Tween 20 were mixed at a ratio of 100:25:2) was addedto quench the reaction. After allowing to stand at room temperature for15 min, the resulting reaction product of inorganic phosphorus withmalachite green was colorimetrically determined at a wavelength of 610nm. In addition, the amount of the inorganic phosphoric acid in thereaction solution free of potassium chloride was measured in the samemanner, which was subtracted from the inorganic phosphoric acid amountin the presence of potassium chloride to determine the proton,potassium—adenosine triphosphatase activity. The inhibitory rate (%) wasdetermined from the activity value of the control and the activityvalues of various concentrations of the test compound, and the 50%inhibitory concentration (IC₅₀) of the proton, potassium—adenosinetriphosphatase was determined. The results are shown in Table 24.

Experimental Example 2

Human liver cancer-derived cell line HepG2 (ATCC No. HB-8065) waspassaged using Dulbecco's Modified Eagle medium (DMEM; Invitrogen)containing 10% fetal bovine serum (FBS; TRACE SCIENTIFIC LTD.), 1 mmol/Lsodium pyruvate (Invitrogen), 2 mmol/L L-glutamine (Invitrogen), 50IU/mL penicillin (Invitrogen) and 50 μg/mL streptomycin (Invitrogen) at5% CO₂. 37° C. The test reagent was prepared with DMSO to 10 mM, andfurther diluted with DMEM medium containing 0.5% FBS, 1 mmol/L sodiumpyruvate, 2 mmol/L L-glutamine, 50 IU/mL penicillin and 50 μg/mLstreptomycin to a final concentration of DMSO of 0.1%. HepG2 (2×10⁴cells/well) was cultured on a 96 well white plate (Costar) with the testreagent at 5% CO₂, 37° C. After culture for one day, the intracellularATP content was measured using ATPLite™ (PerkinElmer Life Sciences). Theresults are shown in Table 24 (n≧3, average value±SD) as a relativevalue (%) to control (without addition of drug) at 30 μM.

TABLE 24 H+/K+-ATPase inhibitory ATP content Example No. activity (IC₅₀,nM) (%, 30 μM) 2 13 45.2 5 65 73.9 24 34 76.5 8 22 87.9 29 41 71.5 348.9 53.6 41 43 86.7 44 48 78.5 47 58 81.8 74 210 95.2

From the results of Table 24, it is clear that compound (I) of thepresent invention has a superior H⁺/K⁺-ATPase inhibitory activity, andfurther shows low cytotoxicity.

Industrial Applicability

Since compound (I) of the present invention shows a superior proton pumpinhibitory effect (while conventional proton pump inhibitors such asomeprazole, lansoprazole etc. form a covalent bond with a cysteineresidue of H+/K+-ATPase and irreversibly inhibit the enzyme activity,since compound (I) inhibits the proton pump (H+/K+-ATPase) activityreversibly and in a K+ antagonist inhibitory manner to consequentlysuppress acid secretion, it is sometimes referred to as apotassium-competitive acid blocker: P-CAB or an acid pump antagonist(ACPA or APA)), it can provide a clinically useful pharmaceuticalcomposition for the prophylaxis and/or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, erosive esophagitis, refluxesophagitis, symptomatic gastroesophageal reflux disease (symptomaticGERD), functional dyspepsia, gastric cancer, stomach MALT lymphoma, orgastric hyperacidity; or an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress. Since compound (I) shows low toxicity andis superior in water-solubility, in vivo kinetics and efficacyexpression, it is useful as a pharmaceutical composition. Moreover,since compound (I) is stable even under acidic conditions, which enablesoral administration of the compound as a conventional tablet and thelike without formulating an enteric-coated preparation. This has aconsequence that the preparation of tablet and the like can be madesmaller, which is advantageous in that it is easily swallowed bypatients having difficulty in swallowing, particularly the elderly andchildren. In addition, since a sustained release effect afforded byenteric-coated preparations is absent, expression of a gastric acidsecretion-suppressive action is rapid, and alleviation of symptoms suchas pain and the like is rapid.

This application is based on patent application Nos. 2005-250356 and2006-100626 filed in Japan, the contents of which are incorporated infull herein by this reference.

1.1-[5-(2-Fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof.